Lower aliphatic acids, salts and derivatives thereof



3,24Z,l85 Patented Mar. 22, 1966 inc (l-PYRIDYL CARBOXY R QUINOLYLCARBOXY- 3-INDOLYL)-LOWER ALIPHATIC ACIDS, SALTS AND DERIVATIVES THEREOFTsung-Ying Sheri, Westfield, N.J., assignor to Merck & Co., Inc.,Rahway, N.J., a corporation of New Jersey No Drawing. Filed Oct. 7,1963, Ser. No. 314,503

Claims. (Cl. 260-2943) This application is a continuation-in-part of mycopending application, Serial No. 164,615, filed January 5, 1962, nowabandoned which was a continuation-in-part of my application, Serial No.97,434, filed March 22, 1961, now abandoned.

This invention relates to new chemical compounds More particularly, itrelates to a new class of compounds of the indole series. Still moreparticularly, it is con cerned with new a-(3-indolyl)-lower aliphaticacids having a pyridine or quinoline carboxylic acyl radical attached tothe nitrogen atom of the indole ring. It is concerned further withsalts, esters and amide derivatives of such compounds. It relates alsoto the synthesis of such substances.

The new aroyl and heteroaroyl indolyl aliphatic acid compounds of thisinvention have the general structural formula:

in which R may be a pyridine, quinoline, isoquinoline or a substitutedpyridine or quinoline radical in which the substituents may be halogen,lower alkyl, lower alkylthio, lower alkoxy, trifluoromethyl, phenoxy,lower alkanoyl, cyano, carb-lower alkoxy, carbamyl, lower alkylsulfonyl, benzylthio, phenylthio, lower alkylphenylthio, mercapto,nitro, amino, di(lower alkyDamino, lower alkanoylamino, hydroxy, orbenzyloxy;

R may be hydrogen, lower alkenyl or lower alkyl;

R may be hydrogen or lower alkyl;

K, may be hydrogen, lower alkoxy, fluorine, lower alkyl ortrifiuoromethyl;

R may be hydrogen, lower alkyl lower alkoxy, nitro, amino, di(loweralkyl)amino, lower alkanoylamino, lower alkanoyl, bis(hydroxy loweralkyl)amin-o, 1-pyrrolidino, 4-methyl-l-piperizinyl, 4-morpholinyl,cyano, amino lower alkyl, di(lower alkyl)amino lower alkyl,trifiuoromethyl, halogen, di(lower alkyl)sulfamyl, benzylthio, loweralkylbenzylthio, lower alkoxy benzylthio, halogenobenzylthio, benzyloxy,lower alkylbenzyloxy, lower alkoxybenzyloxy, halogenobenzyloxy, loweralkenyl, lower alkenyloxy, l-azacyclopropyl, cyclopropylmethoxy orcyclobutylmethyloxy;

and M may be OH, NH lower alkoxy, benzyloxy, OZ

where Z is a cation or OY where Y is the structure:

h R HGH-C o- N/' R2 R4 In the most preferred compounds of the invention,R is a lower alkyl, lower alkoxy, nitro, amino, or substituted amino.Examples of the alkyl and alkoxys are methyl,

ethyl, propyl, t-butyl, methoxy, ethoxy, i-propoxy and the like. R isnot limited to this class ofsubstituents, however, and may, if desired,represent substituents such as hydrogen, aryl, aryloxy, hydroxy,mercapto, halo, pseudohalo such as CF CHI- or other haloalkyls, nitro,amino, alkylamino, acylamino, haloalkyl, cyano, sulfamyl, sulfoxide,aminomethyl, substituted aminomethyl, carboxy, carboalkoxy groups.

A critical feature of the new compounds described herein is the presenceof a pyridine or quinoline carboxylic acyl radical attached to the N-lposition of the indole. These acyl groups may be further substituted inthe aromatic ring with hydrocarbon groups or with functionalsubstituents. Thus, suitable acyl substituents are the picolinoyl,nicotinoyl, isonicotinoyl, isoquinoline and quinoline carboxylic groups.The aromatic rings of such groups may contain, and in the preferredcompounds do contain, at least one functional substituent. Thissubstituent may be a hydroxy or an etherified hydroxy (hydrocarbonoxy)group such as a lower alkoxy, e.g., methoxy, ethoxy, isopropoxy,propoxy, and alkenyloxy such as allyloXy, and aryloxy or aralkoxy group,e.g., phenoxy, benzyloXy, halobenzyloxy, lower alkoxybenzyloxy and thelike. It may be a nitro radical, a halogen such as chlorine, bromine,iodine or fluorine, an amino group or a substituted amino group,representative examples of which that might be mentioned are acylamino,amine oxide, ketimines, urethanes, lower alkylamino, lower dialkylamino,amidine, acylated amidines, hydrazine or a substituted hydrazine,alkoxyamines and sulfonated amines. Further, it may be a mercapto or asubstituted mercapto radical of the type exemplified by alkylthio groupssuch as methylthi-o, ethylthio, and propylthio and arylthio oraralkylthio groups, e.g., benzylthio, phenylthio and loweralkylphenylthio. The N-l aroyl radical may, if desired, be haloalkylatedas with trifluoromethyl, trifluoroethyl, perfiuoroethyl, ,6- chloroethylor like substituent, acylated as with acetyl, propionyl, benzoyl andlike acyl groups. In addition, the invention embraces compounds whereinthe aroyl radical contains a cyano, or dialkylsulfonamido radical.

Further, it may contain a carboxy substituent, or a derivative thereof,such as an alkali metal salt or a lower alkyl ester of the carboXyradical, an aldehyde, azide, amide, hydrazide and the like, or analdehyde derivative of the type represented by acetals or thioacetals.In the preferred compounds, the N-l .aroyl radical is isonico tinoyl andthe functional substituent is in the para position of the six-memberedring.

The a-(3-indolyl)-aliphatic acids described herein are preferably loweraliphatic acids such as a-(3-indolyl) derivatives of acetic, propionic,butyric, valeric and like acids. Lower alkyl esters, salts and theamides of such aliphatic acids represent an additional aspect of theinvention. The esters are important intermediates in the synthesis ofthe free acids, and in many cases are themselves of importance as endproducts. The preferred esters are the lower alkyl esters such as themethyl, ethyl, propyl or t-butyl compounds and the benzyl, p-halobenzyland like esters.

The salts of these new oc-( l-pyridyl carboxy or quinolinecarboxy-3-ind-olyl)-lower aliphatic acids can be obtained by treatmentof the free acid with base under mild conditions. In this manner theremay be obtained alkaline metal salts such as the sodium and potassium,the aluminum or magnesium salts or salts of alkaline earth metals,examples of which are barium and calcium. Salts of organic amines suchas dimethylamine, morpholine, methyl cyclohexylamine or glucosamine maybe obtained by reacting the acid with the appropriate organic base. Theamides included within this invention are conveniently synthesized byfirst preparing the amide of an a-(3-indolyl)-lower aliphatic acidunsubstituted at the 1-position 3 and then acylating said compound bythe process described hereinbelow. Such amides are conveniently obtainedby reacting the free acid with urea or treating the appropriate acidchloride with ammonia.

The 2-p-osition of the indole ring nucleus (R in the above formula) maybe hydrogen although it is preferred that there be present at thisposition of the molecule a hydrocarbon radical having less than ninecarbon atoms. Lower alkyl groups such as methyl, ethyl, propyl or butylare the most satisfactory, but lower alkenyl radicals also can be used.

The following compounds are representative of those contemplated by thisinvention and which may be prepared by the procedure discussedhereinbelowf Methyl-a-[1-(2-chloronicotinoyl)-2-rriethyl-5-methoxy-3-indolyl] -acetate,

methyl-a-[1-(6-fluoropicolinoyl)-2,5-dimethyl-3 indolyl] acetate,

methyl-a-[1-(6-methylthionicotinoyl)-2-methyl-5- methoXy-3-indolyl]-acetate,

a-[1-(6-methoXynic-otinoyl)-2-methyl-5-methoxy- 3-indolyl]-propionicacid,

a-(1-isonicotinoyl-2-methyl-5-methoxy-3 -indolyl acetamide,

a-( 1-picolinoyl-2-methyl-S-methoxy-3-indolyl acetamide,

ethyl-a-1-(2,6-dichloroisonicotinoyl) -2-methyl-5- methoxy-S-indolyl]-propionate,

benzyl-a- 1- (quinaldoyl -2-methyl-5-methoxy3 indolyl] -acetate,

and the like.

The a-(l-pyridine or quinoline carboxy-3-indolyl)-lower aliphatic acidsand derivatives thereof described herein are synthesized by acylation ofthe a-(3-indolyl)-lower aliphatic acid, ester or amide having thedesired substituents at the 2- and S-positions of the ring nucleus. Itis preferred to carry out the acylation on an ester or amide derivativeof the lower aliphatic acid. In those cases where the free acid isdesired, the ester may be converted under suitable reaction conditionsto the free acid. It has been observed that the l-acyl substituent iseasily hydrolyzed under conditions normally employed for saponificationof an ester to the free acid. For this reason, care must be taken inconverting the a-(1-acyl-3- indolyl)-lower aliphatic acid esters to thecorresponding free acids. It has been found that one convenient methodof accomplishing this conversion comprises acylation of the benzyl esterand subsequent hydrogenolytic removal of the benzyl ester.Alternatively, other esters such as the t-butyl esters, which areamenable to selective removal by other treatment, such as heating above210 C. or by heating at 25110 C. in the presence of a catalytic amountof an aryl sulfonic acid or other acids, may be utilized. When, insteadof an ester, the amides of these acids are prepared, the free acids areformed by reaction of the amides with a stoichiometric quantity ofnitrous acid in an inert solvent.

The acylation reaction is conducted by one of two methods. One suchconsists of treating the a-(3-indolyl)- lower aliphatic acid startingmaterial with an alkali metal hydride such as sodium hydride to forme.g., a sodium salt and then intimately contacting said salt with thepyridine or quinoline carboxylic acid halide in an anhydrous solventmedium. It is preferred to employ solvents such as dimethylformamide,dimethylformamide-benzene, benzene, toluene or xylene. It is preferredto carry out the acylation at about room temperature although lowertemperatures may be employed if the particular reactants are undulysusceptible to decomposition.

An alternative and (with these basic heteroaroyl acids) greatlypreferred method of :acylating the 1-position is by use of a phenolicester of the 'acylating acid, such as the p-nitrphenyl ester. Thislatter is prepared by mixing the acid and p-nitrophenol intetrahydrofuran and adding dicyclohexyl carbodiimide intetrahydro-furane slowly. The di'cyclohexylurea which forms is removedby filtration: and the nitrophenylester is recovered from the filtrate.Alternatively, there can also be used the anhydride, azide orthiophenolic ester of the acylating acid. Whichever is used, theacylationo'f the a-(3-i'ndolyl)-lower aliphatic acid starting materialis achieved by forming a sodium salt of said material with sodiumhydride in an anhydroussolvent and adding the nitrophenylester. Becauseof the basic character of these aroyl acids, this method is preferredover' the acid chloride method for pyridine and quinoline carboxyindoles.

The u(1-3-indolyl)-lower aliphatic acid compounds of this invention havea high degree of anti-inflammatory activity and are effective in theprevention and inhibition ofgranuloma tissue formation. Certain of thempossess. this activity in high degree and are of value in the treatmentof arthritic and dermatological disorders and in like conditions whichare responsive to treatment with antiinflammatory agents. In addition,the compounds of this invention have a useful degree of antipyreticactivity. For these purposes, they are normally administered orally intablets of capsules, the optimum dosage depending, of course, on theparticular compound being used and the type and severity of infectionbeing treated. Although the optimum quantities of these compounds ofthis invention to be used in such manner will depend on the compoundemployed and the particular type of disease condition treated, oral doselevels of preferred compounds in the range of 1.0-2000 mg. per day areuseful in control of arthritic conditions, depending on the activity ofthe specific compound and the reaction sensitivity of the patient.

The indolyl aliphatic acid compounds employed as starting material inthe reaction discussed above, and having the formula:

3 CHCOE where R R R and R have the previously defined meanings and E isa hydrocarbonoxy radical having less than nine carbon atoms or -NH maybe synthesized in various ways. When R is hydrogen or methyl, it is preferred to form such compounds by reacting together an appropriatelysubstituted phenylhydrazine and a substituted levulinic ester acide toform an intermediate phenylhydrazone which cyclizes under the reactioncon" ditions to the indole compound where R R R and E are as above, andR is hydrogen or methyl. The reaction is normally carried out in a loweralkanol such as methanol, ethanol, isopropanol or butanol containing anacid such as hydrochloric, hydrobromic, sulfuric or acetic acid or inaqueous mineral acid such as concentrated hydrochloric, hydrobromic,sulfuric or acetic acid, or other Lewis acids such as ZnCl BF SnCL; andthe like. The acid serves as a catalyst in the condensation and ringclosure reactions leading to the 1- unsubstituted indole. When thesubstituted levulinic esters are used, the nature of the ester is notcritical, although it is preferred to utilize a lower alkyl ester, e.g.,the methyl, ethyl, propyl, isobutyl or isopropyl compound. To avoid thepossibility of transesterification the alcohol used as the solventmedium is preferably the same as the alcohol moiety of the ester. When Ris hydrogen, it is convenient to employ the aldehyde in the form of anacetal, e.g., methyl y,' -dimethoxy butyrate. An acid addition salt ofthe phenylhydrazine react-ant, for example the hydrochloride, isnormally preferred over the free base for practical reasons, althoughsuch salts and the base are equivalent in the reaction itself.

Formation of the a-(3-indolyl) aliphatic acid, or ester thereof, isbrought about at elevated temperatures, good results being obtained byrefluxing the reaction mixture for at least about minutes. Longerreaction times are not harmful and may be used if desired. The desiredcompound is recovered from the reaction mixture and purified bytechniques such as solvent extraction, chromatography and/ordistillation. Since the l-unsubstituted esters are low melting solids,they are conveniently purified by distillation under reduced pressure.They are saponified by treatment with an alkali metal hydroxide.

The substituted phenylhydrazines employed as one of the startingmaterials in this synthesis are prepared by known methods. Oneconvenient method is by diazotization of the appropriately substitutedaniline to give the diazo compound, treatment of the latter withstannous chloride to form a tin complex, and decomposition of thiscomplex to the phenylhydrazine with sodium hydroxide.

The l-acyl group in a-(l-acyl-3-indolyl) aliphatic acids and esters ofthis invention are, as has been mentioned earlier, easily hydrolyzedunder the conditions normally used to saponify an ester. For thisreason, the benzyl ester of the intermediatea-(l-unsubstituted-Faindolyl) acids are a convenient starting material.These are obtained by forming the free a-(1-unsubstituted-3- indolyl)aliphatic acid and esterifying this with benzyl alcohol in an inertsolvent with an acid catalyst (sulfuric, aryl sulfonic acids, etc.).Alternatively, the intermediate benzyl ester is synthesized directly byusing the benzyl ester of the proper levulinic acid in the originalsynthesis of the indole ring, or is formed by base catalyzed esterexchange from other esters. After acylation of the indole nitrogen ofthese benzyl ester intermediates, the benzyl group can be removedclearly by hydrogenolysis, a process which leaves the ll-acyl groupuntouched.

Alternatively, it is possible first to produce an indole of the formula:

where R R and R have the same meaning as before, and then to introducethe carboxylic acid residue at the 3-position. This is accomplished bytreating the indole of the above formula under Mannich reactionconditions with formaldehydedialkylamine to produce a substitutedgramine, subsequently reacting this latter compound with an alkali metalcyanide in a lower alkanol, and finally hydrolyzing with a strong basesuch as sodium or potassium hydroxide.

While this method of introducing the aliphatic acid residue at the3-position after elaboration of the indole ring is, of course, generallyapplicable to compounds having the structure shown above, it isparticularly useful for making compounds of this invention wherein R isan alkyl radical other than methyl, such as the 2-ethyl, 2-propyl,2-allyl and like substances. Compounds of the above formula,unsubstituted in the 3-position, are readily prepared following theprocedures set forth in columns 2 and 3 of US. Patent No. 2,825,734.Products where R is acyloxy, halo, cyano, carboxy, carbalkoxy, alkyl,aryl,

6 aralkyl, nitro or hydrocarbonoxy are prepared via the synthesisbeginning from a substituted 2-nitro benzalde' hyde or Z-nitrotoluene.

The synthesis of various compounds of this invention having on theindole ring system a 5'substituent which has a nitrogen attached to thehomocyclic ring of the indole is generally based on the S-nitrocompound. This is transformed into the desired S-substituent. Suchtransformation may be before or after acylation of the l-position,depending on the extent to which the desired S-substituent may interferewith the acylation. If such interference is possible, the 1-acylationshould be carried out on the S-nitro indole and the nitro latertransformed into the desired S-Substituent. Such transformation can becarried out in a number of ways. Reduction of the 5- nitro groups givesa S-amino group. Reaction of the amino with alkyl halides gives mono anddialkyl amino groups. If the alkyl halide is a dihaloalkylene group(e.g., l,4-dibromobutane) a heterocyclic ring (e.g., pyrrolidino) isformed. Similarly, bis(,8-chlorethyl)ether will give an N-morpholinocompound. Alkylation can also be carried out simultaneous withreduction, as e.g., with formaldehyde and Raney nickel and hydrogen.Acylation can similarly be carried out on the 5-amino compounds or onthe S-nitro (with simultaneous reduction) to give S-acylamido compounds.The S-amino group can be reacted with isocyanates to give S-ureidocompounds.

EXAMPLE 1 (A) Ethyl-w(2-methyl-5-methoxy 3 indolyl)-propionate.Asolution of 25 g. of p-methoxyphenylhydrazine hydrochloride and 20 g. ofethyl OL-I'IIGtlbYl levulinate in 250 ml. of 2 N ethanolic hydrochlorideis heated on a steam bath for a few minutes. An exothenmic reactiontakes place With the separation of ammonium chloride. The reaction flaskis removed from the steam bath and the mixture allowed to reflux gentlyuntil the initial reaction subsides. The mixture is again heated on astream bath under reflux for 30 minutes, and then concentrated in vacuoto a volume of about ml. The concentrate is diluted with about 400 ml.of water and extracted with ether. The resulting ethereal extract is:washed with a saturated solution of sodium bicarbonate, and with water,and dried over anhydrous sodium sulfate. The dried solution is filteredand evaporated to a dark brown syrup which is purified by chromatographyover about 1 lb. of acid-washed alumina in a 2%" ID. column usingmixtures of ether and petroleum ether (v./v. 1:9 to 1:1) as eluent. Thelight yellow syrup so obtained is distilled in a short-path distillationapparatus and the product collected at B.P. l50-153 C. (0.25 mm.). Thedistillate of ethyl-rx-(Z-methyI-S-methoxy 3 indolyl)-propionatecrystallizes on trituration with petroleum ether, MJP' 53-55 .5 C. Onrecrystallization from a mixture of ether and petroleum ether themelting point is unchanged.

Calcd. for C H O N: C. 68.94; H, 7.33; N, 5.36. Found: C, 69.23; H,7.31; N, 5.60.

When the methyl, propyl, isopropyl or benzyl ester of tit-methyllevulinic acid is employed in the above reaction in place of the ethylester, there is obtained methyl-a-(2-methyl-5 methoxy 3indolyl)-propionate, propyl-a-(Z-methyl-S-methoxy 3 indolylypropionate,isopropyl-a-(2-tmethyl-5-methoxy-3-indolyl) propionate, orbenzyl-a-(2-methyl 5 methoxy-3-indolyl)-propionate, respectively.Alternatively, when an ester of levulinic acid is used as startingmaterial in the above process, the corresponding ester ofu-(2-methyl-5-methoxy- 3 -indolyl)- acetic acid is obtained.

(B) Ethyl-u-(Zj-dimethfl 3 ind0lyl)-pr0pianate.- 20 g. ofpmet-hylphenylhydrazine hydrochloride and 20 g. of ethyl a-methyllevulinate are added to 250 ml. of 2 N ethanolic hydrogen chloride andthe mixture warmed until reaction sets in. After the initial exothermicreaction stops, the mixture is refluxed for about /2 hour and thenconcentrated in vacuo to about /3 volume. 400

ml. of water are added and the aqueous solution extracted with ether.The ether extracts are washed with sodium bicarbonate solution, and withWater, then dried over sodium sulfate. The ether solution isconcentrated to a small volume in vacuo and chromatographed overacidwashed alumina (1 lb. of alumina in a 2% LD. column). The materialeluted with ether-petroleum ether (v./v. 9:1 to 1:1) is distilled in ashort-path distillation apparatus. Ethyl-a-(ZJ-dimethyl 3indolyl)-propionate distills at 150170 (bath temp.)/l mm., and cry--stallizes on trituration with petroleum ether, M.P. 88- 88.5 C.

When a lower alkyl or benzyl levulinate is employed in place of ethyla-methyl levulinate, lower alkyl or benzyl-(2,5-dimethyl-3-indolyl)acetate is produced.

EXAMPLE 2 A suspension of 2.3 g. (0.046 m.) of 50% sodiumhydride-mineral oil in 250 ml. of dimethylformamide is stirred for 20minutes under nitrogen with ice-cooling. Then 8.64 g. (0.035 m.) ofethyl-u-(2-methyl-5-methoxy- 3'indolyl)-propionate is added and themixture stirred for 20 minutes. 8.6 g. (0.046 m.) of nicotinoyl chloridein 50 ml. of dimethylformamide is added dropwise over a period of 30minutes. The mixture is stirred in an icebath for 5 hours undernitrogen. It is then poured into a mixture of 500 ml. of ether, 5 ml. ofacetic acid and 1 l. of iced water. The organic products are extractedwith 3x300 ml. of ether. The ether solutions are combined and washedWith a large quantity of Water, and dried over sodium sulfate. Thesolution is filtered, evaporated to near dryness and the residue chargedonto a 300 g. alumina column. The ethyl-a4l-nicotinoyl-Z-methyl-5-methoxy 3 indolyl)-propionate is eluted with 10% ether inpetroleum ether. It is obtained on concentration of the eluates todryness.

The nicotinoyl chloride starting material is obtained by heating amixture of 0.15 m. of nicotinic acid and 0.18 m. of thionyl chloride ona steam bath for 1 hour. About 20 ml. of benzene is then added andboiled off. The remaining solution is centrifuged and diluted withpetroleum ether. On cooling, the acid chloride hydrochloride separates.

When methyl-(2=methyl-5-methoxy 3 indolyl)-acetate is employed as thestarting material in the above process, there is obtained methyl (1nicotinoyl 2 methyl-5- methoxy-3-indolyl)-acetate.

EXAMPLE 3 M ethyl-1 -nictin0yl-2-methyl-5 -metlz0xy-3 -ind0lyl acerate(A) p-NitrophenyI-nicotinate.ln a 500 ml. round bottom flask (allequipment flame dried) is added 13.9 g. of p-nitrophenol and .3 g.nicotinic acid in 250 ml. dry tetrahydrofuran. Through a dropping funnelis added over 30 minutes 20.6 g. of dicyclohexylcarbodiimide in 100 ml.of dry tetrahydrofuran. The reaction is allowed to run overnight withstirring. The dicyclohexylurea which forms during the reaction isfiltered. The filter cake is washed with dry tetrahydrofuran. Thesolution is evaporated to dryness. The solid is taken up in benzene andwashed with sodium bicarbonate solution and then with water and driedover anhydrous sodium sulfate. The solution is concentrated under vacuumto drymess. The solid p-nitrophenyl is then recrystallized from benzene.

(B) Methyl-1-nic0tinoyl-2-methyl 5 methoxy 3 ind0lylacetate.-In a 250ml. round bottom flask (flame dried. equipment) is placed at 0 C. withnitrogen, 100 ml. of dry dimethylformamide with 10.5 g. of methyl-a-(Z-methyl-5-methoxy-3-indolyl)-acetate. To this is added 2.5 g. of 50%sodium hydride mineral oil mixture. After the mixture is stirred for 30minutes there is added over 15 minutes a solution of 6.7 g. ofp-nitrophenyl nicotinate in ml. dry dimethylformamide. The reactionmixture is stirred for 4 hours at 0 C. under nitrogen followed bystirring under nitrogen at room temperature over night. The reactionmixture is then poured into an ice-Waterether solution containing a fewml. of acetic acid and the layers are separated. The aqueous phase iswashed. with ether and the ether extracts are combined and dried oversodium sulfate. To the ether solution is added a saturated solution ofhydrogen chloride gas in dry ether. The ether is decanted off, leaving aheavy oil. The oil is washed with ether followed by an addition ofaqueous sodium bicarbonate solution. The product is then extracted withether. The ether layer is dried. over anhydrous sodium sulfate andconcentrated to dryness. The product,methyl-(l-nicotinoyl-2-methyl-5-methoxy-3 indolyl)-acetate, iscrystallized from benzene-Skellysolve B.

EXAMPLE 4 Methyl 1-(6-chl0r0nic0tin0yl) -2-methyl-5-meth0xy-3-indolylacetate The procedure of Example 3 is followed using 6-chloronicotinicacid in place of nicotinic acid in part A and the product thereof in theprocedure of part B, to yield methyl1-(6-chloronicotinoyl)-2-methyl-5-methoxy-3 indolyl acetate.

Similarly, when Z-chloronicotinic acid, 4-chloronicotinic acid,S-chloronicotinic acid, 2-fluoronicotinic acid, S-fluoronicotinic acid,6-fiuoronicotinic acid, 2-bromonicotinic acid, S-bromonicotinic acid,6-iodonic0tinic acid, 2-methyl 5 iodonicotinic acid, 4,5,6trichloropicolinic acid, 4-bromoquinaldic acid, 5-chloroquinaldic acid,6- chloroquinaldic acid, 3,4-dibromoquinaldic acid,4,7-dichloroquinaldic acid, 2-bromoisonicotinic acid,3-chloroisonicotinic acid, 3-fluoroisonicotinic acid, 6-fluoropicolinicacid, 5-cyano-6-methyl 2 trifiuoromethylnicotinic acid (obtained. bysaponification of the ethyl ester with aqueous caustic at reflux),Z-o-fiuorophenylquinoline-4- carboxylic acid,2-metl1yl-5-carbethoxy-6-trifiuoromethylnicotinic acid, (obtained by theaction of nitrous acid on ethyl-5-carbamyl-6-methyl-2trifluoromethylnicotinate), 5-dimethylcarbamyl-6-methyl-2trifluoromethylnicotinic acid (from the ethyl ester by mildsaponification with weak caustic at room temperature) or3-fiuoroisonicotinic acid are used instead of nicotinic acid in theprocedure of Example 3, the corresponding methyl 1-acyl-2-methyl-5-methoxy-3indolyl acetates are obtained.

EXAMPLE 5 1-is0nic0tilt0yl-2-methyl-5-meth0xy-3-ind0lyl-acetic acid (A)Z-methyl-S-methoxy 3 indolylacetic anhydride.-- Dicyclohexylcarbodiimide(10 g., 0.049 mole) is dissolved in a solution of2-methyl-5-methoxy-3-indolylacetic acid (22 g., 0.10 mole) in 200 ml. ofTHF, and the solution is allowed to stand at room temperature for 2hours. The precipitated urea is removed by filtration, and the filtrateis evaporated in vacuo to a residue and flushed with Skellysolve B. Theresidual oily anhydride is used without purification in the next step.

(B) t-Butyl 2-methyl-S-methoxy-3-ind0lylacetate.-t- Butyl alcohol (25ml.) and fused zinc chloride (0.3 g.) are added to the anhydride frompart A. The solution is refluxed for 16 hours and excess alcohol isremoved in vacuo. The residue is dissolved in ether, washed severaltimes with saturated bicarbonate, water and saturated salt solution.After drying over magnesium sulfate, the solu tion is treated withcharcoal, evaporated, and flushed several times with Skellysolve B forcomplete removal of alcohol. The residual oily ester (18 g., 93%) isused without purification.

(C) t-Bmyl 1-is0nic0tinoyl-2-methyl-5-methoxy-3-ind0lylacetate.A stirredsolution of ester (18 g., 0.065 mole) in dry dimethylformamide (450 ml.)is cooled to 4 in an ice bath, and sodium hydride (4.9 g., 0.098 mole,50% susp.) is added in portions. After 15 minutes, p-

nitrophenyl isonicotinate (prepared by the procedure of Example 3A usingisonicotinic acid instead of nicotinic acid, (0.085 mole) indimethylformamide is added dropwise during 10 minutes, an the mixture isstirred for 4 hours at C. under nitrogen followed by overnight at roomtemperature. The mixture is then poured into an ice water ether mixturecontaining a few ml. of acetic acid. The layers are separated and theaqueous phase is extracted with ether. The ether solutions are combined,dried over sodium sulfate and to the solution is added a saturatedsolution of dry HCl in ether. The ether is decanted, leaving a heavy oilwhich is washed with water followed by aqueous NaHCO solution. Theproduct is then extracted with ether and the extract is dried overanhydrous Na SO Evaporation of the ether yields tbutyl 1-isonicotinoyl2amiethyl-5-methoxy-3-indolyl acetate which is purified bychromatography on a column of neutral alumina using ether-petroleumether v./v. 20- 60%) as the e'luent.

(D) 1-is0nicotinoyl-2-methyl-5-methoxy-3-ind0yl acetic acid.A mixture ofl g. of the ester prepared in part C and 0.1 g. powdered porous plate isheated in an oil bath at 210 with magnetic stirring under a blanket ofnitrogen for about 2 hours. No intensification of color (pale yellow)occurs during this period. After cooling under nitrogen, the product ispartitioned between a mixture of ether and dilute ammonium carbonate.The aqueous solution is filtered with suction to remove ether,neutralized with acetic acid, and diluted Wit-h ethanol to precipitatethe zwitter ion. The crude product,l-isonicotinoyl-Z-methyl-S-methoxy-3-indolyl acetic acid isrecrystallized from aqueous ethanol and dried in vacuo.

EXAMPLE 5A Methyl 1- (4-is0quin0lyl carboxy2-methyl-5-meth0xy-3-ind0lylacetate The procedure of Example 3A isfollowed, using isoquinoli-ne-4-carboxylic acid instead of nicotinicacid, to produce p-nitrophenyl isoquinoline-4-carboxylate. This is thenused in the procedure of Example 3B to produce methyl-1-(4-isoquinolinecarboxy)Z-methyl-S-methoxy-3- indolyl acetate.

When isoquinoline-l-carboxylic acid and isoquinoline- 6-carboxylic acidare used instead of the 4 isomer, the correspondingly l-substituedesters are obtained.

EXAMPLE 6 Ethyl ot-(1-pic0linoyl-Z-mcthylJ-methoxy-S-indolyl)-propiolmte The procedure of Example 3A is followed, using picolinicacid instead of nicotinic acid to product p-nitrophenyl picolinate. Thisis then used in the procedure of Example 3B, using ethyla-(2-methyl-5-methox -3- i-ndolyl)-proprionate instead of methyl2-methyl-5-methoxy- 3-indolyl acetate, to produce ethyl-a41-picolinolyl2- methyl-5-methoxy-3-indolyl -'propionate.

EXAMPLE 7 J -(o-methylnicotinoyl)-2-m thyl-5-metIz0xy-3-indolyl-aceticacid (A) A solution of 15 g. ofmethyl-(Z-methyl-S-methoxy-3-indolyl)-acetate and 0.2 g. of sodium in 60ml. of benzyl alcohol is slowly fractionated over a period of 4 /2 hoursthrough a Vigreux column to remove methanol. The excess benzyl alcoholis then removed by distillation at 60 C. (2.5 mm.) to give a residue of18.6 g. of benzyl-(2-methyl-5-rnethoxy-3-indolyl)-acetate.

(B) 10 g. of the benzyl ester obtained above is added to 6.6 g. of 51%sodium hydride-mineral oil emulsion in 260 ml. of dimethylformamideaccording to the procedure of Example 2. This mixture is treated asdescribed in that example with 6-methylnicotinoyl chloride (prepared byheating excess SOCl followed by removal of excess thionyl chloride invacuo) and the reaction mixture 10 worked up by the above-describedprocess using a chromatographic column of 340 g. of alumina and elutingwith 20-30% ether in petroleum ether. From these eluates there isobtainedbenzy1-[1-(6-methylnicotinoyl)-2-methyl-5-methoxy-3-indolyl]-acetate.

(C) 1.5 g. of the ester obtained in Part B above is added to 20 ml. ofethyl acetate containing a drop of acetic acid and reduced catalyticallyat room temperature in the presence of palladium on charcoal catalyst.When the reduction is complete the catalyst is removed by filtration andthe filtrate evaporated. to a crystalline residue. This residue .isrecrystallized from aqueous ethanol to give1-(6-methylnicotinoyl)-2-methyl-5-methoxy- 3-indolyl acetic aid.

EXAMPLE 8 1-(4-ethylnic0tin0yl) -2-methyl-5-mezhoxy-3-ind0lyl aceticacid The procedure of Example 5 is followed, using 4-ethylnicotinic acidin place of iso-nicotinic acid, to produce 1-(4ethylnicotinoyl)-2-methyl-5-methoxy-3-indolyl)acetic acid. Similarly,when any of the following acids are used in equivalent quantity in placeof isonicotinic acid, the corresponding1-acyl-2-n1ethyl-5-methoxy-3-indolyl acetic acid is formed:

Z-methylnicotinic acid,

4-methylnicotinic acid,

3-methyl quinoline-Z-carboxylic acid,

8-methyl quinaldic acid,

3-methyl isonicotinic acid,

2-dibutylaminoquinoline-4-carboxylic acid,

2-nitronicotinic acid,

6-nitronicotinic acid,

6-methoxynicotinic acid,

2,6-dipropoxyisonicotinic acid,

2,6-dibutoxyisonicotinic acid,

4-phenoxynicotinic acid,

4-benzyloxyquinaldic acid,

4-methoxyquinaldic acid,

3-(p-butoxyphenoxy)-2,6-dimethylquinoline-4-carboxylic acid,

5-cyanoisonicotinic acid,

2-cyanonicotinic acid,

Z-acetylnicotinic acid,

3-phenylthioisonicotinic acid,

2-(5-chloro-o-tolylthio)-6-methyl nicotinic acid,

2-benzylthioison-icotinic acid,

2-ethylthioisonicotinic acid,

2-ethylsulfonylisonicotinic acid, or

6-methylthionicotinic acid.

EXAMPLE 9 I-(Z-quinolylcarboxy)-2-mcthyl-5-methoxy-3-indolyla-propiom'cacid (A) Z-mezhyl 5 methoxy-S-indolyl-a--pr0pi0nicanhydridc.-Dicyclohexylcarbodiimide (9 g., 0.044 mole) is dissolved in asolution of 2-methyl-5-methoxy-3-indoly1-otpropionic acid (21 g., 0.09mole) and 200 ml. of THF, and the solution is allowed to stand at roomtemperature for 2 hours. The precipitated urea is removed by filtration,and the filtrate is evaporated in vacuo to a residue and flushed withSkellysolve B. The residual oily anhydride is used without purification.

(B) t-Butyl 2 methyl-5-meth0xy-3-ind0lyl-arpropionate.t-Butyl alcohol(25 ml.) and fused zinc chloride (0.3 g.) are added to the aboveanhydride. The solution is refluxed for 16 hours, and excess alcohol isremoved in vacuo. The residue is dissolved in ether, washed severaltimes with saturated bicarbonate, Water and saturated salt solution.After drying over magnesium sulfate the solut-ion is treated withcharcoal, evaporated, and flushed sev eral times with Skellysolve B forcomplete removal of alcohol. The residual oil ester (14 g.) is usedwithout purification.

(C) t-Butyl I-(Z-quinoline carboxy)-2-methyl-5-me-IhOXy-3-il1d0lyl-ot-[NOPlOIZdZ.A stirred solution of ester from part B(20 g., 0.69 mole) in 450 ml. of dry dimethylformamide is cooled to 4 inan ice bath and sodium hydried (5.2 g., 0.10 mole, 50% susp.) is addedin portions. After the mixture is stirred for 10 minutes, a DMF solutionof 2-quinoline carboxy chloride (0.091 mole) (prepared by heating theacid in with SOC1 followed by evaporation in vacuo) is added in portionsduring 10 minutes, and the mixture is stirred for 7 hours at roomtemperature without replenishing the ice bath. The mixture is thenpoured into 1 1. of 5% acetic acid, extracted with ether, washedthoroughly with water, bicarbonate, saturated salt solution, dried overmagnesium sulfate, treated with charcoal, and evaporated in vacuo to aresidue. This is dissolved in ether, mixed with 100 g. of acid-washedalumina, and evaporated in vacuo to dryness. The residue is placed abovea column of 300 g. of neutral alumina in Skellysolve B. After Washingwith Skellysolve B, the product is eluted with 5% ether-Skellysolve B.

(D) ]-(2-quin0line carboxy)-2-methyl-5-meth0xy-3-indolyl-wpropionicacid.-The pyrolysis is carried out in the same manner as with t-butyl1-isonicotinoyl-2-methyl 5-methoxy-3-indolyl acetate (of Example 5D).The product is recrystallized from aqueous ethanol orbenzene-Skellysolve.

EXAMPLE 10 Methyl (Z-methyl-5-nitr0-3-ind0lyl) acetate A solution of 40g. of levulinic acid in 300 ml. of hot water is added to a solution of65 g. of p-nitrophenylhydrazine hydrochloride in 700 ml. of hot Waterwith stirring. After about one-half hour, the hydrazone derivative iscollected in a filter, Washed with water and dried at 110 in vacuo. Theyield is 84 g., M.P. 175179.

An amount of 42 g. of the above hydrazone is added to a solution of 120g. of fused zinc chloride in 100 ml. of absolute ethanol and the mixtureis refluxed for 18 hours. The cooled solution is poured into dilutehydrochloric acid with stirring, and the insoluble gummy materialseparated is extracted with hot ethanol. The ethanolic extract isevaporated in vacuo to a syrup, which is redissolved in ether. The ethersolution is extracted with 10% sodium carbonate several times.Acidification of the aqueous solution gave a crude product whichrecrystallizes from chloroform to give(2-methyl-5-nitro-3-indolyl)acetic acid, M.P. 238.

The above acid is treated with a mixture of 3 g. of sulfuric acid and 40ml. of methanol at the reflux temperature for 6 hours. The methyl esteris obtained as a yellow crystalline product, M.P. 132-40 afterrecrystallization from benzene.

Similarly, methyl-tx- 2-methyl-5-nitro-3-indolyl -prpionate is preparedby using an equivalent amount of etmethyl levulinic acid as the startingmaterial.

EXAMPLE 11 Methyl (Z-methyl--amino-3-ind0lyl) acetate 3 g. ofmethyl(2-methyl-5-nitro-3-indolyl)acetate is dissolved in 300 ml. drymethanol and reduced in hydrogen in an autoclave with Raney nickel ascatalyst. After the theoretical amount of hydrogen is taken up thecatalyst is removed by filtration. The catalyst and reaction flask arewashed with methanol. The methanol solution is evaporated to dryness.The product is crystallized from benzene, M.P. 144-145".

Micr0analysis.Calcd. C, 66.03; H, 6.47; N, 12.84. Found: C, 65.96; H,6.29; N, 12.56.

EXAMPLE 12 Methyl[2-methyl-5-(1'-pyrr0lidin0)-3-ind0lyl] acetate In a125 ml. flask is placed 80 ml. of ethanol. To this is added 1.0 g. ofmethyl (2-methyl-5-amino-3-indolyl)- acetate, 0.99 g. of1,4-dibromobutane and 0.975 g. of anhydrous sodium carbonate. Thismixture is stirred at reflux temperature in a nitrogen atmosphere for 6hours. The reaction mixture is then filtered and the filtrate isconcentrated in vacuo to a small volume and diluted with ether. Thissolution is then washed with water 2X, dried with anhydrous sodiumsulfate and concentrated in vacuo to dryness. The product is absorbed on6 g. of silica gel. The product is then chromatographed over 30 g. ofsilica gel using as eluant from v./v. 3:1 ether-petroleum ether toether. The eluted material is combined and crystallized frombenzene-Skellysolve B. M.P. 1l7118.

Micr0almlysis.Calcd. C, 70.56; H, 7.40; N, 10.29. Found: C, 70.77; H,7.72; N, 10.00.

When ethylene dibrornide is used instead of dlblOIl'lO- butane, theproduct obtained is the 5-(1-azacyclopropyl) ind-olyl compound.

EXAMPLE 13 Methyl (1-is0nicotinoyl-Z-methyl-S-(]'-pyrr0lia'in0)-3-ind0lyl acetate The procedure of Example 3B is followed using methyl[2 methyl-5-(1-pyrrolidino)-3-indolyl]acetate in place of the indoleester from 3A used in that example to produce methyl[1-isonicotinoyl-2-methyl-5-( 1-pyrrolidino)- 3-indolyl] acetate.

' EXAMPLE 14 Methyl-(1 -nic0tinoyl-Z-methyl-5-nitr0-3-ind0lyl) acetateIn a dried 250 ml. flask is placed 3.9 g. of methyl-(2-methyl-5-nitro-3-indolyl) acetate in ml. dry dirnethylforrnamide. Tothis solution cooled to 0 C. is added 0.8 g. of 50% sodiumhydride-mineral oil. This is stirred under nitrogen for 30 minutes. Tothis is added dropwise 4.0 g. of p-nitrophenyl isonicotinate in 15 ml.of dry dimethylformamide over a 5-minute period. The reaction mixture isstirred 4 hours at 0 C. under nitrogen and then stirred overnight atroom temperature under nitrogen. It is then poured into an iceWater-ether solution containing a few milliliters of acetic acid. Theether layer is separated and the aqueous layer is Washed with ether. Tothe combined ether layers after drying over Na SO is added a saturatedsolution of hydrogen chloride gas in dry ether. The ether layer isdecanted and the residue is washed with ether followed by an addition ofaqueous NaHCO solution. The alkaline solution is then extracted withether and the ether layer is dried and evaporated in vacuo. The product,methyl l-nicotinoyl- 2-methyl-5-nitro-3-indolyl) acetate is crystallizedfrom dry ether-Skellysolve.

EXAMPLE 15 Methyl-(1-nic0tinoy[-2-methyl-5-dimethylamino-3- indolyl)acetate To a solution of 0.387 g. of methyl-a-(l-nicotinoyl-2-methyl-5-nitro-3-indolyl) acetate in 20 ml. of distilleddimethoxyethane is added 1.5 ml. of glacial acetic acid and 0.5 ml. of a37% solution of aqueous formaldehyde. This mixture is reduced with Raneynickel at 40 p.s.i. and room temperature. After the theoretical amountof hydrogen has reacted, the reaction mixture is filtered, concentratedin vacuo to a small volume and diluted with ether. The ether solution iswashed with sodium bicarbonate, then with water, dried with anhydroussodium sulfate and concentrated in vacuo. The product is methyl (1nicotinoyl-2-methyl-5-dirnethylamino-3-indolyl) acetate.

EXAMPLE 16 Methyl-(1-nic0tin0yl-2-melhyl-5-acetamin0-3-ind0lyl) acetateTo 0.388 g. of methyl-(1-nicotinoyl-2-methyl-5-nitro- 3-indolyl) acetatein 30 ml. of anhydrous ethyl acetate is added 0.306 g. acetic anhydride.The mixture is reduced with Raney nickel at room temperature and 40p.s.i. After the theoretical amount of hydrogen has been absorbed, thecatalyst is removed by filtration. The solu- EXAMPLE l7BenzyI-(Z-methyl-5-nitro-3 indolyl) acetate In a dry 250 ml. flask isplaced 80' ml. dry benzene and 20 ml. benzyl alcohol. To this is added3.0 g. of 2-methyl-5-nitro-3-indolyl acetic acid and 0.2 g. ofptoluenesulfonic acid. This slurry (which clears on heating) is heatedto reflux under nitrogen. The water formed during the reaction iscollected in a Stark and Dean tube. The reaction is stopped when thedistillate is clear (about 2 hours). The excess benzyl alcohol isremoved in vacuo. The residue is dissolved in benzene and Washed withsodium bicarbonate followed by water, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The product is absorbed on 15 g. ofacidwashed alumina and chromatographed over 75 g. of acidwashed alumina.The product is eluted with v./v. 1:1- 3:1 ether-benzene. The eluate isevaporated and the combined product is crystallized frombenzene-Skellysolve B. M.P. 147-148.

"Micranalysis.-Calc. C, 66.66; H, 4.97; N, 8.64. Found: C, 66.83; H,4.77; N, 8.52.

EXAMPLE 18 "Benzyl-(1-nie0tinoyl-2-methyl-5-nitr0-3-ilzd0lyl) acetate Ina dry 125 ml. flask is placed 3.0 g. of benzyl-(2- methyl5-nitro-3-indolyl) acetate in 60 ml. of dry dimethylformamide. To thissolution, cooled to 0 C. in nitrogen atmosphere is added 0.475 g. of 50%sodium hydride-mineral oil. This is stirred for 30 minutes. Then 2.32 g.of p-nitrophenyl nicotinate in ml. of dry dimethylformamide is addeddropwise over a 5-minute period. The reaction mixture is stirred at 0 C.for 4 hours under a nitrogen atmosphere followed by stirring at roomtemperature under nitrogen overnight. It is then poured into an icewater-ether mixture. The ether layer is separated and the aqueous layeris washed with ether. The combined ether extracts are acidified with anether solution of dry hydrogen chloride and the ether is decanted. Theresidue is washed with ether and then stirred with aqueous NaHCOsolution. The alkaline mixture is extracted with ether and the extractsare dried with anhydrous sodium sulfate and concentrated in vacuo todryness. The product, benzyl (l-nicotinoyl-Z- methyl-5-nitro-3-indolyl)acetate, is crystallized from benzene-Skellysolve B.

EXAMPLE 19 Methyl-e-(I-nicotinoyl-2-methyl-5-amin0-3-indolyl) propionate0.025 mole of methyla-(1-nicotinoyl-2-methyl-S-nitro- 3-indolyl)propionate in 100 ml. of ethanol is hydrogenated inthe presence of 120mg. of 10% palladium or -charcial catalyst at 40 psi. at roomtemperature. After 0.075 m. of hydrogen has been consumed, thehydrogenation is stopped, and the solution filtered to remove thecatalyst. The filtrate is concentrated to dryness in vacuo to givemethyl-a-(1-nicotinoyl-2-rnethyl-5-amino- 3-indolyl) propionate.

EXAMPLE 20 Methyl 1-(3-hydr0xyis0nic0tin0yl)-2-methyl-5-meth0xy-3-ind0lyl acetate (A) p-Nitrophenyl 3-benzyl0xyisonicotinate-Theprocedure of Example 3A is followed, using 3-hydroxyisonicotinic acid inplace of nicotinic acid, to produce pnitrophenyl-3-hydroxyisonicotinate.To a solution of this ester (0.1 mole) in ml. dry dimethylformamideunder nitrogen is added 0.1 mole sodium hydride in 50% mixture withmineral oil. The mixture is stirred 30 minutes at room temperature andthen 0.12 mole of benzyl chloride is added over 15 minutes. The mixtureis stirred for 4 hours at 0 C. under nitrogen, followed by stirringuntil room temperature is reached. The mixture is poured into ice waterand ether containing acetic acid and the layers are separated. Theaqueous layer is washed with ether, the extracts are combined, washedwith aqueous bicarbonate and dried and concentrated in vacuo. Theresidue is p-nitrophenyl-3-benzyloxyisonicotinate.

(B) Methyl] (3-benzyloxyisonicotinoyl)-2-methyl-5- meth0xy-3-ind0lylacetate-The procedure of Example 3B is followed, using pnitrophenyl-3-benzyloxyisonicotinate in place of the nicotinate usedtherein. The prodnot is 1-(3-benzyloxyisonicotinoyl)-2-methyl-5-methoxy-3-indolyl acetic acid.

(C) Methyl 1 (3-hydroxyis0nic0tia0yl)-2-methyl-5- methoxy-3-indolylacetate.A solution of 0.1 mole of the product of Par-t C in ml. ofmethanol is shaken with 3 g. of palladium on charcoal and hydrogen untilhydrogen uptake ceases. The catalyst is filtered and the filtrate istaken to dryness in vacuo to yield1-(3-hydroxyisonicotinoyl)-2-methyl-5-methoxy-3-indolyl acetic acid.

(D) When the procedures of parts A, B and C are followed, usingZ-hydroxyisonicotinic acid, S-hydroxyquinoline-Z-carboxylic acid,6-hydroxynicotinic acid or 4,6- dihydroxynicotinic acid (doublequantities of reagents needed in part A) in place of 3-hydroxynicotinicacid, the corresponding l-acyl indole compounds are obtained.

EXAMPLE 21 (A) Methyl[1-nicotinoyl-2-methyl-5-bis(,B-hydroxyethyl)amin0-3indolyl]acetate-Amixture of 0.02 mole of methylw(l-nicotinoyl-2-methyl-5-amino-3-indolyl) propionate, 0.044 mole ofethylene oxide and 0.03 mole of acetic acid in 300 ml. dimethoxyethaneis heated to 100 for 18 hours in an autoclave. The mixture is thendiluted with water and filtered to yield crude methyl-[1- nicotinoyl 2methyl-S-bis(B-hydroxyethyl)amino-3-indOIyH-propionate.

When an equivalent amount of propylene oxide is used in the aboveprocedure in place of the ethylene oxide, there is obtainedmethy1-[l-nicotinoyl'2-methyl-S-bis(hydroxypropyl amino-3-indolyl-propionate.

(B) Methyl [1 nic0tin0yl-2-methyl-5-(4'-methyl-1'-piperazinyl)-3-indolyl] acetate-The product of A is stirred at 0 inpyridine with two mole proportions of p-toluenesulfonyl chloride untilthe reaction is substantially complete. The mixture is poured into waterand the 5-bis(p-toluenesulfonyloxyethyl)amino compound is isolated. Thisis dissolved in benzene and one mole proportion of methylamine is added.The mixture is allowed to stand at room temperature for 3 days. Themixture is poured into iced water containing two equivalents of sodiumcarbonate and extracted with ether immediately. Evaporation of the etheryields methyl-[l-nicotinoyl-Z- methyl-5-(4'-methyl-1-piperazinyl)-3-indolyl] acetate.

Either of the above products that form part A or part B, when used inthe procedure of Example 7, gives the corresponding free acid.

EXAMPLE 22 A solution of tosyl chloride (0.1 mole) in 200 ml. benzene isadded dropwise with stirring to a solution of methyl u[1-nicotinoyl-2-methyl-5-bis-(fi-hydroxyethyl) amino-3-indolyl1acetate(0.1 mole) and pyridine (0.3 mole) in 300 ml. benzene at roomtemperature over a period of one hour. The mixture is then heated underreflux for 3 hours, washed with Water, dried over sodium sulfate andevaporated to a syrup. Chromatography of the syrup on an aluminum columnusing 3050% (v./ v.) either in petroleum ether as the eluent givesmethyl-[1- nicotinoyl-2-methyl-5-(4-morpholinyl -3-indolyl] acetate.

The above product, when used in the procedure of Example 7, gives thecorresponding free acid.

EXAMPLE 23 (A) 2 methyl-5-cyan0-3-ind0lyl acetic acid methyl ester'.Asolution of p-cyano phenylhydrazine (0.1 mole) and levulinic acid (0.1mole) in 200 ml. concentrated hydrochloric acid is heated at 90 for 20minutes and diluted with iced water (400 ml.). The crude product whichseparates is extracted with ether and chromatographed on a silica gelcolumn to give Z-methyl-S-cyano- 3-indolyl acetic acid using 2050%(v./v.) ether and petroleum ether as the eluent.

The methyl ester is prepared by treatment with diazomethane in etheruntil the yellow of diazomethane persists and the mixture is evaporated.

(B) Methyl c (1-nicotinoyl-2-methyl-5-cyan0-3-irzd0lyl)acetate.Acylationof the ester (prepared in Example 23A above) in dimethylformamide withsodium hydride and p-ni-trophenyl nicotinate by the procedure of Example3, gives methyl-(1-nicotinoyl-2-methyl-5-cyano- 3-indolyl acetate.

(C) MethyZ-a-(LniCOtinOyI-Z methyl-S-aminomethyl- 3-ind0lyl)acelate.The-cyano ester prepared in Example 23B is hydrogenated in ethanol in thepresence of Raney nickel and 3 moles of anhydrous ammonia at 2000 psi.at room temperature to give, after filtration of the catalyst andevaporation of the reaction mixture, methyl(1-nicotinoyl-2-'methyl-5-aminomethyl 3-indolyl)acetate which can berecrystallized from aqueous ethanol.

(D) Methyl-(I-nicotinoyl 2-methyZ-S-dimethylaminmmethyl-3-ind0lyl)acetate.Treatment of the above aaminomethyl indole with2 moles of methyl iodide gives the S-dimethylaminomethyl derivative.When ethyliodide is used in place of methyl iodide, theS-diethylaminomethyl derivative is obtained.

(E) When the products of Examples 23C and 23D above are used in theprocedure of Example 7, the corresponding free acids are obtained.

EXAMPLE 24 a- (1-nic0tin0yl-2-methyl-5-meth0xy-3-ind0lyl) butyric acidWhen the procedure of Examples 1 and 2 are followed using ethyl a-ethyllevulinate in place of ethyl a-methyl levulinate, there is obtainedsuccessively ethyl tit-(2- methyl-5-methoxy-3-indolyl)butyrate and ethyl04-(1-1'1lC- otinoyl-Z-methyl-S-methoxy-3-indolyl) butyrate. When thelatter product is used in the procedure of Example 7 the correspondingbutyric acid derivative is obtained.

The starting ethyl a-ethyl levulinate is prepared by alkylation of thesodio derivative of ethyl acetoacetate in ethanol with 1 m. of ethyla-bromobutyrate, followed by hydrolysis and decarboxylation. The a-ethyllevulinic acid obtained in reesterified with 2 N ethanolic hydrogenchloride at reflux temperature for 18 hours.

EXAMPLE 25 6.5 g. (0.02 mole) of a-(l-nicotinoyl-Z-methyl-S-methoxy-3-indolyl)-acetic acid is added to 50 ml. of water which hasbeen flushed with nitrogen. The slurry is stirred under nitrogen and 20ml. of 1.05 N sodium carbonate added with stirring. When a clearsolution is obtained, a solution of 2.2 g. of Al (SO .18H O in 8 ml. ofwater is added with vigorous stirring. The mixture is stirred until itis homogenous and the solid aluminum salt of(1-nicotinoyl-Z-methyl-S-methoxy-3-indolyl) acetic acid, is recovered byfiltration and washed with water and with ethanol,

16 In a similar fashion, there may be prepared the sodium and aluminumsalts as well as other salts, such as the potassium, iron and magnesiumsalts, of the various (3- indolyl) aliphatic acids described in theaccompanying examples.

EXAMPLE 26 1-(p-nicotinoyl-Z-methyl-5-meth0xy-3-ind0lyl) aceticanhydride The procedure of Example 5A is followed using1-(nicotinoyl-Z-methyl-S-methoxy-3-indolyl)acetic acid in place of thel-unsubstituted acid. The product, 1-nicotinoyl-2-methyl-5-methoxy-3-indolyl acetic anhydride, is found on testing to beabout equal to the free acid in the alleviation of inflammation.

When any of the other 1-substituted free indolyl acids herein describedare used in the procedure of Example 5A, the corresponding anhydride isobtained.

EXAMPLE 27 Ethyl-a-(1-nic0tin0yl-2-methyl-5-eth0xy-3-ind0lyl) propionateThe procedure of Example 1A is followed using an equivalent quantity ofp-ethoxyphenylhydrazine hydrochloride in place of themethoxyphenylhydrazine to give ethyl-ir-(2-methyl-5-ethoxy-3indolyl)propionate. When this is used in the procedure of Example 3,there is obtained ethyl-u-( l-nicotin-oyl 2 methyl 5 methoxy 3- indolyl)propionate. This product, when used in the procedure of Example 7,yields the corresponding free a-indolyl propionic acid.

Similarly, when p-propoxy, p-butoxy, p-benzyloxy, p-4-methylbenzyloxy,p-4-methoxybenzyloxy, p-4-chlorobenzyloxy phenylhydrazine are used inthe above procedures, the correspondingly S-substituted indolyl acidsare obtained. When the 1-nicotinoyl-2-methyl-S-benzyloxy- (orsubstituted benzyloxy)-3-indolyl propionic acids so prepared aresubjected to catalytic hydrogenation over palladium, there is obtaineda-(1-nicotinoyl-2-methyl-5- hydroxy-3-indolyl)propionic acid. 7

When the procedure of Example 1A is followed using in place of thep-methoxyphenylhydrazine, equivalent amounts of p-ethylphenylhydrazine,p-butylphenylhydrazine, p-trifiuoromethylphenylhydrazine,p-chlorophenylhydrazine and p-fluorophenylhydrazine (each obtainable bydiazotization of the corresponding p-substituted aniline and reductionof the diazo) and the resultant indolyl ester is acylated by theprocedure of Example 3 and further treated by the procedure of Example7, the corresponding 5-substituted indolyl esters and acids areobtained.

When the procedure of Examples IA, 3 and 7 are followed starting withphenylhydrazine, the corresponding S-unsubstituted indolyl esters andacid are produced.

EXAMPLE 28 1-is0l2ic0tin0yl-2-methyl-5-meth0xy-3-ind0lyl-acetamide To asuspension of 1.0 g. of 50% sodium hydride in ml. benzene is added 4.4g. of 2-methyl-5-methoxy-3-indolylacetamide with stirring. Twenty ml. ofdimethylformamide is then added, followed by 2.8 g. isonicotinoylchloride twenty minutes later. The reaction mixture is stirred at roomtemperature for 1 hour and then poured into 400 ml. of ice and water.The precipitate is collected on a filter. The crude product isrecrystallized from ethyl acetate twice.

EXAMPLE 29 1-is0nicotinoyl-2-melhyl-5-methoxy-3-ind0lyl-acetic acid To asolution of 3.2 g. of 1-is0nicotinoyl-2-rnethyl-5-methoxy-3-indolylacetamide in 50 ml. dimethoxyethane containing 1 ml. of12 N hydrochloric acid at 0 is added 0.7 g. of sodium nitrite withstirring. After gas evolution has subsided the mixture is neutralizedwith dilute ammo- 1 7 nium hydroxide, concentrated in vacuo and thendiluted with ethanol to precipitate the product, which is purified byrecrystallization from aqueous ethanol.

EXAMPLE 30 The procedure of Example 1A is followed using an equivalentquantity of each of the following phenylhydrazines in place of thep-methoxyphenyl hydrazines; p-dimethylsulfonamidophenylhydrazine, pbenzylmercaptophenylhydrazine, p-vinylphenylhydrazine.

When the resulting indolyl acid is acylated by the procedure of Example3, the corresponding l-nicotinoyl indolyl acids are obtained.

EXAMPLE 31 Methyl 1-nic0tin0yl-Z-m ethyl--allyloxy-34nd0lyl acetate (A)Methyl 5-hydr0xy-2-methyZ-S-indolyl acetate-A mixture of g. of methyl5-methoxy-2-rnethyl-3-indolylacetate and 50 g. of pyridine hydrochlorideis heated at 180 under nitrogen for minutes. The reaction mixture isthen cooled to about 50, dissolved in 150 ml. of 1.5 N methanolichydrogen chloride and refluxed for 2 hours. After cooling, the solutionis concentrated in vacuo, poured into water and extracted with ether.The ethereal solution is washed with water and extracted three timeswith 50 ml. of 5% sodium hydroxide. The combined aqueous extract isacidified to pH 6 and extracted with ether. After drying ov-er sodiumsulfate, the ethereal solution is evaporated to give methylS-hydroxy-Z-methyl- 3-indolyl acetate, recrystallized from benzene, MP.158-170" (3.4 g.).

(B) MethyI-Z-methyl-5-allyloxy-3-indolyl acetate. A mixture of 3.4 g. ofthe S-hydroxyindole, 2.4 g. of allylbromide and 7.5 g. of potassiumcarbonate is stirred at room temperature to 56 for 18 to 6 hours. Thereaction mixture is filtered, concentrated in vacuo to a syrup andchromatographed on 60 g. of silica gel, using v./v. 50% ether inpetroleum ether as eluent to give 0.7 g. of methyl5-allyloxy-2-met-hyl-3-indo lyl acetate as an oil.

(C) 1 nicotinoyl 2 methyl 5 allyloxy 3 indolyl acetate.The procedure ofExample 3 is followed, using the above 5-allyloxy compound in place ofthe 5-methoxy compound to give methyl-l-(p-chlorobenzoyl-2-methyl-5-allyloxy-3-indolyl)acetate, recrystallized from benzene- Skellysolve B.

Similarly, when allyl bromide is replaced by an equivalent amount ofcyclopropylmethyl bromide, cyclobutylmethyl bromide and isopropylbromide, the corresponding 5 cyclopropylmethoxy, 5 cyclobutylmethoxy, 5isopropoxyanalogs are obtained.

EXAMPLE 32 S-trifluoromethylphenylhydrazine 250 mls. of chilledconcentrated hydrochloric acid is slowly added withst-irring, to 0.40 ofa mole of freshly distilled 3-aminobenzotrifluoride, which is keptcooled in an ice-salt bath. When the temperature of the above suspensionis 0", a precooled solution of 0.40 of a mole of sodium nitrite in 125mls. of water is added through a separating funnel, whose tip isimmersed below the surface of the suspension. The addition is carriedout over 75 minutes, maintaining the reaction below 3. A chilledsolution of 0.89 mole of stannous chloride dihydrate in 200 mls. ofconcentrated hydrochloric acid is then added dropwise to this stirredand cooled diazonium solution, over a period of three hours. During thisaddition, the temperature is maintained at 0-5" and after the addition,the solution is stirred for an additional hour at 0". The resultingsolid is collected by filtration, pressed as dry as possible and thenshaken with 700 mls. of 25% sodium hydroxide. The yellow mixtureobtained is allowed to stand overnight at room temperature. The mixtureis then extracted with three 300 ml. portions of benzene. The combinedfiltered ben- 18 zene solution is dried over 20-30 gm. of potassiumhydroxide. Distillation, under vacuum, of this benzene solution gives3-trifluoromethylphenylh'ydrazine.

When equivalent amounts of Z-aminobenzotrifluoride,4-methoxy-3-trifluoromethylaniline, 4 methoxy 2 trifiuoromethylaniline,4 nitro 3 trifluoromethylaniline, 4 nitro 2 trifluoromethylaniline, or 4methyl 3 trifiuoromethylaniline is employed in the above procedure inplace of 3-aminobenzotrifiuoride, there is obtained 2-trifluoromethyl'phenylhydrazine, 4methoxy-S-trifluoromethylphenyl'hydrazine 4 methoxy 2.trifluoromethylhydrazine, 4 nitro 3 trifluoromethylphenylhydrazine, 4nitro 2-trifluoromethylphenylhydrazine, or 4-methyl-3-trifluoromethylphenylhydrazine, respectively.

EXAMPLE 33 Methyl-4 and 6-trzflu0romethyl-3-ind0lylacetate 0.2 mole ofmethyl dimethoxybutyrate is added, dropwise with stirring, to a solutionof 0.2 mole of 3- trifluoromethylphenylhydrazine in 75 ml. of 50% aceticacid. The mixture is allowed to stir at room temperature for threehours, and then 300 ml. of water is added. The crude hydrazone whichseparates out is collected and dried in vacuo. 0.04 mole of the driedhydrazone is then intimately mixed with 0.85 mole of freshly fused zincchloride. To this mixture is added, with stirring, for 5 minutes at roomtemperature, ml. of glacial acetic acid and 5 ml. acetic anhyride. Themixture is then refluxed for one hour and cooled to room temperature.This resulting mixture is poured onto chopped ice and Water and allowedto stand overnight in a refrigerator. The solid is collected andprecipitated by filtration and chromatographed on acid-washed aluminaand eluted with ether-petroleum ether (v./v. 550%). The two isomerswhich are obtained, namely, methyl-(4-trifluoromethyl 3 .indolyl)acetateand methyl-(6-trifluoromethyl-3-indolyl)acetate are differentiated bynuclear magnetic resonance spectroscopy.

When equivalent amounts of 4-methoxy-3-trifiuoromethylphenylhydrazine, 4nitro-3-trifluoromethylphenylhydrazine, or 4 methyl 3trifluoromethylphenylhydrazine is employed in the above procedure inplace of 3- trifluoromethylphenylhydrazine, there is obtained bothisomers of each, namely, methyl-(5-methoxy-4-trifiuoromethyl3-indolyl)acetate, methyl-(5-methoxy-6-trifluoromethyl 3indolyl)acetate; methyl-(5-nitro-4-trifluoromethyl 3 indolyl)acetate;methyl-(5-nitro-6-trifluoromethyl 3 indolyl)acetate; ormethyl-(5-methyl-4-trifluoromethyl 3 indolyl)acetate;methyl-(S-methyl-6- trifiuoromethyl-3-indolyl)acetate, respectively.

Similarly, when equivalent amounts of Z-trifiuoromethylphenylhydrazine,4 methoxy Z-trifiuoromethylhydrazine, 4 nitro2-trifluoromethylphenylhydrazine, or 4 methyl2-trifluoromethylphenylhydrazine is employed in place of 3trifluoromethylphenylhydrazine, there is obtained methyl(7-trifluorornethyl-3-indolyl) acetate; methyl (5 methoxy 7trifluoromethyl 3- indolyl)acetate; methyl (5 nitro7-trifiuorometl1yl-3- indolyl)acetate, or methyl (5methyl-7-trifluoromethvl- 3-indolyl)acetate, respectively.

EXAMPLE 34 Methyl-ot-[4 0r 6-triflu0r0methyl-3-ind olyl]propiolzate Whenthe procedure of Example 40 is followed, usingmethyl-wy-dimethoxy-u-rnethyl-butyrate in place ofmethyl-y;y-dimethoxybutyrate, there are obtained two isomers, namely,methylax-(4-trifluoromethyl-3-indolyl) propionate andmethyl-a46-trifluoromethyl-3-indolyl) propionate.

When equivalent amounts of 4-methoxy-3-trifiuoromethylphenylhydrazine,or 4-methyl-3-trifluoromethylphenylhydrazine is employed in place of3-trifluoromethylphenylhydrazine, there are obtained both isomers ofeach, namely, methyl-ot-(5-methoxy-4-trifluoromethyl-3-indolyl)propionate, methyl c (-methoxy-6-trifluoromethyl 3indolyl)propionate;methyl-a-(5-methyl-6-trifluoromethyl-3-indolyl)propionate, respectively.

Similarly, when equivalent amounts of 2-trifluoromethylphenylhydrazine,4 methoxy-2-trifluoromethylphenylhydrazine or4-methyl-2-trifluoromethylphenylhydrazine is employed in place of3-trifiuoromethylphenylhydrazine, there is obtainedmethyl-ot-(7-trifluoromethyl-3-indolyl) propionate,methyl-u-(5-methoxy-7-trifluoromethyl-3-indolyl)propionate ormethyl-a-(5-methyl-7-trifluoromethyl-3-indolyl)propionate, respectively.

EXAMPLE 35 Methyl- (2-methyl-4 or 6-trifluor0methyl-3-ind0lyl) acetateWhen the procedure of Example 33 is followed, using methyl levulinate inplace of methyl-vq-dimethoxybutyrate, there is obtained two isomers,namely, methyl(2- methyl-4-trifiuoromethyl-3-indolyl)acetate and methyl-(Z-methyl-6-trifluoromethyl-3-indolyl) acetate.

When equivalent amounts of 4-methoxy-3-trifluoromethylphenylhydrazine,4-nitro-3-trifluoroinethylphenylhydrazine, or4-methyl-3-trifluoromethylphenylhydrazine is employed in place of3-trifiuoromethylphenylhydrazine, there is obtained both isomers ofeach, namely, methyl- (5 methoxy 2 methyl 4 trifluoromethyl-3-indolyl)acetate, methyl-(5-methoxy-2-methyl 6-trifluoromethyl-3-indolyl)a-cetate; methyl (2 methyI-S-nitro-4-trifluoromethyl 3indolyl)acetate, methyl (2 methyl 5- nitro 6 trifiuoromethyl 3indolyl)acetate; or methyl- (2,5 dimethyl 4 trifiuoromethyl 3indolyl)-acetate, methyl (2,5 dimethyl 6 trifiuoromethyl 3 indolyl)acetate, respectively.

Similarly, when equivalent amounts of Z-trifluoromethylphenylhydrazine,4-methoxy-2-trifluoromethylphenylhydrazine,4-nitro-2-trifiuoromethylphenylhydrazine, or 4-methyl-Z-trifiuoromethylphenylhydrazine is employed in place of3-trifiuoromethylphenylhydrazine, there is obtainedmethyl-(2-methyl-7-trifluoromethyl-3-indolyl)-acetate,methyl-(S-methoxy-2-methyl-7-trifiuoromethyl-3-indolyl -acetate,methyl-( Z-methyl-S-nitro-7-trifluoromethyl-3-indolyl)-acetate, ormethyl-(2,5-dimethyl-7-trifluoromethyl-3-indolyl)-acetate, respectively.

EXAMPLE 36 M ethyl-a- (Z-methyl-trffluorometltyI-S-indolyl propionateWhen the procedure of Example 33 is followed, using methyl-a-methyllevulinate in place of methyl-'yq-dimethoxybutyrate, there is obtainedtwo isomers, namely, methyl on (2 methyl 4 trifiuoromethyl 3 indolyl)propionate and methyl-ot-(2-methyl-6-trifluoromethyl-3-indolyl)-propionate.

When equivalent amounts of 4-methoxy-3-trifluoromethylphenylhydrazine or4-methyl-3-trifluoromethylphenylhydrazine is employed in place of3-trifluoromethylphenylhydrazine, there is obtained both isomers ofeach, namely, methyl-a-(5-methoxy-2-methyl-4-trifiuoromethyl-3-indolyl)-propionate, methyl-m45-methoxy-2-methyl-6-trifluoromethyl-3-indolyl)-propionate; or methyI-a-(LS- dimethyl 4trifluoromethyl-3-indolyl)-propionate and methyl 0c (2,5 dimethyl 6trifiuoromethyl 3 indolyl) propionate, respectively.

Similarly, when equivalent quantities ofZ-trifluoromethylphenylhydrazine, 4 methoxyZ-trifluoromethylphenylhydrazine, or4-methyl2-trifluoromethylphenylhydrazine is employed in place of3-trifluoromethylphenylhydrazine, there is obtainedmethyl-ot-(2-methyl-7-trifluorornethyl-3-indolyl)-propionate ormethyl-a-(2,5-dimethyl-7-trifluoromethyl-3-indolyl)-propionate,respectively.

(A) A solution of 0.05 mole ofmethyl-(4-trifiuoromethy1-3-indolyl)acetate and 0.01 mole of sodium in60 ml. anhydrous benzyl alcohol is slowly fractionated over a period of4 /2 hours through a Vigreux column to remove methanol. The excessbenzyl alcohol is removed by distillation at and 2.5 mm. to give aresidue of crude benzyl- (4-trifiuoromethyl-3-indolyl) acetate.

(B) A suspension of 0.046 mole of 50% sodium hydride-mineral oil in 250ml. of dimethylformamide is stirred for 20 minutes under nitrogen, withice-cooling. Then 0.035 mole of the benzyl ested obtained above in partA is added and the mixture stirred for 20 minutes. 0.046 mole ofp-nitrophenyl nicotinate in 50 ml. of dimethylformamide is addeddropwise over a period of 30 minutes. The mixture is stirred in an icebath for 5 hours under nitrogen, then poured into a mixture of 500 ml.of ether, 5 ml. of acetic acid and 1 l. of iced Water. The organicproducts are extracted with 3x300 ml. of ether. The ether solutions arecombined and acidified with an ether solution of dry HCl. The ether isdecanted and the residue is Washed with ether and then mixed withaqueous NaHCO The mixture is extracted with ether and the extracts aredried over sodium sulfate. The solution is then evaporated to neardryness and the residue charged onto a 300 g. alumina column. Thebenzyl-(l-nicotinoyl- 4-trifiuoromethyl-3-indolyl)acetate is eluted withetherpetroleum ether (5-50% v./v.).

(C) 0.02 mole of the ester obtained in part B is added to 50 ml. ofethyl acetate containing a drop of acetic acid and is reducedcatalytically at room temperature in the presence of palladium oncharcoal catalyst. Upon completion of the reduction, the catalyst isremoved by filtration and the filtrate evaporated to yield l-nicotinoyl-4-trifluoromethyl-3-indolyl acetic acid.

When the methyl esters described in Examples 34, 35, 36 and 37 are usedin the above procedures, the corresponding l-nicotinoyl-3-indolyl aceticor 3-indolyl-a-propionic acid derivatives are obtained.

When, in the above procedure, the p-nitrophenyl esters of isonicotinicacid, picolinic acid, 6-chloronicotinic acid or S-chloropicolinic acidare used in place of the nicotinate, the corresponding l-acyl-S-indolylacids are obtained.

EXAMPLE 38 Methyl [1 (S-mercaptoisonicotinoyl) -2-methyl-5-meth0xy-S-indolyl] acetate The procedures of Examples 20A, 20B and 20C arefollowed, using 3-mercaptoisonicotinic acid in the procedure of Example20A and the product thereof successively in 20B and 20C, to producemethyl 1-(3-mercaptoisonicotinoyl)-2-methyl-5-methoxy-3-indolyl acetate.

EXAMPLE 39 (1 -ntc0tinoyLS-hydroxy-4-triflu0r0methyl-3-indolyl aceticac't'd 0.001 mole of 1-nicotinoyl-5-methoxy-4-trifiuoromethyl- 3-indolylacetic acid is added portionwise, with stirring, to 1.5 g. of pyridinehydrochloride at 220. On cooling, the residue is dissolved in a smallamount of water and extracted with ether to remove starting material.The aqueous solution is adjusted to pH 6.5 and diluted with ethanol toprecipitate the zwitter ionl-nicotinoyl-S-hydroxy-4-trifiuoromethyl-3-indolyl acetic acid, which isrecrystallized from aqueous ethanol.

EXAMPLE 40 Pro pyl- 1 -nic0tin'0y l-4-trifltt0r0methyl-3indolyl acetateA solution of 0.0054 mole of N,N-dicyclohexylcarbodiimide in 60 ml. ofanhydrous tetrahydrofuran is added to a solution of 0.005 mole of1-nicotinoyl-4-trifluoromethyl-B-indolyl acetic acid and 0.0054 mole ofn-propyl alcohol in 25 ml. of anhydrous tetrahydrofuran. The reactionmixture is shaken vigorously and allowed to stand at room temperatureovernight. The dicyclohexylurea is filtered 01% and 2 ml. of glacialacetic acid is added to the filtrate. The mixture is allowed to standfor one hour. The solution is filtered and about 200 ml. of ether isadded to the filtrate. This filtrate is then extracted well with water.The ether solution is dried over sodium sulfate and concentrated invacuo. The crude material is chromatographed on neutral alumina usingether-petroleum ether (v./v. 20-50% to obtain propyl 1-nicotinoyl-4-trifiuoromethyl-3-indolyl acetate.

EXAMPLE 41 2-flu0r0-4-methylpheny[hydrazine 150 ml. of concentrated HClis slowly added with stirring to 0.1 mole of 2-fluoro-4-methylaniline.When the temperature of this su spension is at l, 0.1 mole of 40% sodiumnitrite solution is added. The above addition is carried out over 75minutes, maintaining the temperature below A chilled solution of 0.3mole of stannous chloride in 75 ml. of concentrated hydrochloric acid isthen added, dropwise, to this stirred and cooled diazonium solution,over a period of three hours. During this addition the temperature ismaintained at 05 and after the addition the solution is allowed toremain at 0 for several hours. The mixture is then filtered and the cakewashed with cold sodium chloride solution. This solid is then added to100 m1. of saturated sodium acetate solution, extracted with ether andthe ether dried. This crude 2-fluoro-4-methylphenyl hydrazine is finallyisolated and purified as its hydrochloride.

. When equivalent amounts of 3-fluoro-4-methyl-aniline, 2 fluoro 4methoxyaniline, 3 fluoro 4 methoxyaniline, 2 fluoro 4 nitroaniline or 3fluoro 4- nitroaniline is used in the above procedure in place of 2fluoro 4 methylaniline, there is obtained 3 fluoro- 4methylphenylhydrazine, 2 fluoro 4 methoxy- .phenylhydrazine, 3 fluoro 4methoxyphenylhydrazine, 2 fluoro 4 nitrophenylhydrazine, or 3 fluoro 4-nitrophenylhydrazine, respectively.

EXAMPLE 42 Methyl-4 0r 6-flu0r0-3-indolyl acetate 0.07 mole of3-fluorophenylhydrazine and 0.08 mole of methyl-" ,'y-dimethoxybutyrateare added to 250 ml. of 2 N ethanolic hydrogen chloride and the mixturewarmed until reaction sets in. After the initial exothermic reactionstops, the mixture is refluxed for about one-half hour and thenconcentrated in vacuo to about one-third volume. Four hundred ml. ofwater are added and the aqueous solution extracted with ether. The etherextracts are washed with sodium bicarbonate solution, water, and thendried over sodium sulfate. The ether solution is concentrated to a smallvolume in vacuo and chromatographed over 200 g. of acid-washed alumina.The material is eluted with ether-petroleum ether (v./v. 50-60%) anddistilled in a short-path distillation apparatus. Both isomers, namely,methyl 4 fluoro 3- indolyl acetate and methyl 6 fluoro 3 indolyl acetateare obtained. The structure of these two isomers are ditferentiated bymeans of nuclear magnetic resonance spectroscopy. When an equivalentamount of 3 fluoro 4 methylphenylhydrazine, 3 fluoro 4methoxyphenylhydrazine is employed in place of 3-fluorophenylhydrazine,there is obtained both isomers of each, namely, methyl (4- fluoro 5methyl 3 indolyl)acetate, methyl-(G-fiuoro- S-methyl 3 indolyl)acetate;or methyl (4 fluoro- 5 methoxy 3 indolyl) acetate, methyl (6 fluoro 5-methoxy 3 indolyl)acetate, respectively.

Similarly, when an equivalent amount of 2 fiuorophenylhydrazine, 2fluoro 4 methylphenylhydrazine, 0r 2 fluoro 4 methoxyphenylhydrazine isemployed in place of 3 fluorophenylhydrazine, there is obtained 22methyl (7 fiuoro 3 indolyl)acetate, methyl (7- fluoro 5 methyl 3indolyl)acetate, or methyl (7- fluoro 5 methoxy 3 indolyDacetate,respectively.

EXAMPLE 43 Methyl 0L[4 0r 6-flu0r0-3-ind0lyl]propionate When theprocedure of Example 42 is followed, using methyl 'y,'y dimethoxy amethyl butyrate in place of methyly-dimethoxybutyrate, there is obtainedtwo isomers, namely, methyl a (4 fluoro 3 indolyl)- propionate andmethyl a (6 fluoro 3 indolyl)- propionate.

When an equivalent amount of 3 fluoro 4 methylphenylhydrazine, 3 fluoro4 methoxyphenylhydrazine or 4 nitrophenylhydrazine is employed in placeof 3- fluorophenylhydrazine, there is obtained both isomers of each,namely, methyl a (4 fluoro 5 methyl 3- indolyl) propionate, methyl a (6fluoro 5 methyl- 3 indolyl) propionate; or methyl a (4 fluoro 5- methoxy3 indolyl) propionate, methyl a (6- fluoro 5 methoxy 3 indolyl)propionate, respectively. i

Similarly, when an equivalent amount of 2 fluorophenylhydrazine, 2fluoro 4 methylphenylhydrazine or 2 fluoro 4 methoxyphenylhydrazine isemployed in place of 3 fluorophenylhydrazine, there is obtained methylor (7 fluoro 3 indolyl) propionate, methyl- O6 (7 fluoro 5 methyl 3indolyl) propionate or methyl a (7 fluoro 5 methoxy 3 indolyl)propionate, respectively.

EXAMPLE #4 Methyl-4 0r 6-flu0r0-2-methyl-3-indolyl-acetates When theprocedure of Example 42 is followed, using methyl levulinate in place ofmethyl-v,y-dimethoxybutyrate, there is obtained two isomers, namely,methyl-(4- fluoro 2 methyl 3 indolyl) acetate and methyl- (6 fluoro 2methyl 3 indolyl) acetate.

When an equivalent amount of 3-fluoro-4-methylphenylhydrazine,3-fluoro-4-methoxyphenylhydrazine, or 3-fluoro-4-nitrophenylhydrazine isemployed in place of 3-fluorophenylhydrazine, there is obtained bothisomers of each, namely, methyl-(2,5-dimethyl-4-fluor0-3-indolyl)-acetate and methyl-(2,5-dimethyl 6 fiuoro-3-indolyl)-acetate;methyl-(4-fluoro 5 methoxy-Z-methyl-Iaindolyl)-acetate,methyl-(6-fiuoro-5-methoxy-2-methyl-3- indolyl)-acetate, respectively.

Similarly, when an equivalent amount of Z-fluorophenylhydrazine,Z-fiuoro-4-methylphenylhydrazine, or 2- fluoro-4-methoxyphenylhydrazineis employed in place of 3-fiuorophenylhydrazine, there is obtainedmethyl-(7- fluoro-2-methyl-3-indolyl -acetate, methyl- 2,5 -dimethyl-7-fiuono-3-indolyl)-acetate, ormethyl-(7-fluoro-5-methoxy-2-methyl-3-indolyl -acetate, respectively.

When the procedure of Example 42 is followed using methyl-a-methyllevulinate in place of methyl-'y -dh methoxybutyrate, there is obtainedtwo isomers, namely, methyl-w (4-fluoro -2 methyl-3-indolyl)-propi0nateand mCthYI-OC- 6-fiuoro-2-rnethyl-3-indolyl -pnopionate.

When an equivalent amount of 3-fiuoro-4-methylphenylhydrazine isemployed in place of S-fiuorophenyl hydrazine, there is obtained bothisomers of each, namely, methyl-r142,5-dirnethyl-4-fiuoro 3 indolyl)propionate, methyl-a- (2,5-dimethyl-6-fluoro-3-indolyl -propi0nate, ormethyl-w(4-fluoro-5-methoxy 2 methyl-3-indolyl)-propionate, methyl a (6fluoro-5-methoxy-2-methyl-3-indolyl)-propionate, respectively.

In addition, when an equivalent amount of 2-fluorophenylhydrazine,2-fluoro-4-methylphenylhydrazine is employed in place of3fluorophenylhydrazine, there is obtain edme-thy-l-a-(7-fiuoro-2-methyl-3 indolyl), propionate,methyl-a-(2,5-dimethyl-7-fluoro-3-indolyl) propronate, ormethyl-m-(7-fluoro-5-methoxy-2-methyl 3 indolyl) propionate,respectively.

23 EXAMPLE 45 (A) A solution of 0.05 of a mole of methyl-(4-fluoro-3-indolyl)-acetate and 0.01 of a mole of sodium in 60 ml. of benzylalcohol is slowly fractionated over a period of 4 hours through aVigreux column to remove methanol. The excess benzyl alcohol is thenremoved by distillation at 60 C. (2.5 mm.) to give a residue ofbenzyl-(4-fluoro-3-indolyl)-acetate.

(B) A suspension of 0.046 -m. of 50% sodium hydride-mineral oil in 250ml. of dimethylformamide is stirred for 20 minutes under nitrogen withice-cooling. Then 0.035 m. of the benzyl ester obtained in part A isadded and the mixture stirred for 20 minutes. To the above mixture,0.046 m. of p-nitrophenyl nicotinate in 50 ml. of dirnethylformamide isadded dropwise over a period of 30 minutes. The mixture is stirred in anicebath for 5 hours under nitrogen. It is then poured into a mixture of500 ml. of ether, 5 ml. of acetic acid and 1 l. of iced water. Theorganic products are extracted with 3x300 ml. of ether. The ethersolutions are com.- bined and acidified with an ether solution of dryHCl. The ether is decanted and the residue is washed with ether and thenmixed with aqueous NaHCO The mixture is extracted with ether and theextracts are dried over sodium sulfate. The solution is then evaporatedto near dryness and the residue charged onto a 300 g. neutral aluminacolumn. The crude benzyl-(l-nicotinoyl- 4-fluoro-3-indolyl)-acetate iseluted with ether-petroleum ether (v./v. 1050% (C) 0.02 of a mole of theester obtained in part B is added to 50 ml. of ethyl acetate containinga drop of acetic acid and is reduced catalytically at room temperaturein the presence of palladium on charcoal catalyst. Upon completion ofthe reduction, the catalyst is re moved by filtration and the filtrateevaporated to yield (1-nicotinoyl-4-fluoro-3-indolyl)-acetic acid.

EXAMPLE 46 (A) (6-meth0xy-3-indolyl) -acetic anhydride.0.049 mole ofdicyclohexylcarbodiimide is dissolved in a solution of 0.10 mole of6-methoxy-3-indolyl acetic acid in 200 ml. tetrahydrofuran and allowedto stand at room temperature for 2 hours. The precipitated urea isremoved by filtration and the filtrate is evaporated in vacuo to aresidue and flushed with Skellysolve B. The residual oily anhydrideobtained is used without purification in the next step.

(B) (t-Butyl-tS-methoxy 3 indlyl)-acetate.--25 mls. of t-butyl alcoholand 0.3 gm. of fused zinc chloride are added to the anhydride from partA. The solution is refluxed for 16 hours and the excess alcohol isremoved in vacuo. The residue is then dissolved in ether and washedseveral times with saturated salt solution. The ether extract is driedover magnesium sulfate and the solution treated with charcoal. The ethersolution is then evaporated and flushed several times with Skellysolve Bfor complete removal of the alcohol. This residual oily ester is usedwithout purification in the next step.

(C) (t-butyl-l-nicotinoyl 6 methoxy-3-ind0lyl)-acezate..065 mole of thecrude ester, as obtained in step B, is added to 450 mls. ofdimethylformamide and cooled to 4 in an ice bath. .098 mole of a 50%suspension of sodium hydride is added portionwise to this stirredsolution. After 15 minutes, 0.085 mole of p-nitrophenyl nicotinate isadded over a 10 minute interval. This mixture is then stirred for 9hours, without replenishing the ice bath. At this time, the mixture ispoured into 1 liter of acetic acid and extracted with ether. The ethersolution is acidified with an ether solution of dry HCl. The ether isdecanted and the residue is washed with ether and then mixed withaqueous NaHCO The mixture is extracted with ether and the ether extractis dried over magnesium sulfate. It is then treated with charcoal andevaporated to a residue. The crude product, thus obtained, ischromatographed on 600 gms. of neutral alumina using a mixture of (v./v.1050%) ether-petroleum ether as eluent.

(D) I nicotinoyl-6-meth0xy-3-indolyl acetic acid.--A mixture of 1.0 g.of the ester obtained in step C and 0.1 g. powdered porous plate isheated, with stirring, in an oil bath at 210 C. under nitrogen for 2hours. The product is isolated in the same manner as Example 5D.

(E) 1 nicotinoyl 7 meth0xy-3-ind0lyl acetic acid.- When the procedure ofparts A, B, C and D is used, starting with 7-methoxy-3-indolyl aceticacid instead of the 6-methoxy isomer, there is obtained 1-nicotinoyl-7-methoxy-3-indolyl acetic acid.

EXAMPLE 47 1-nic0tinoyl-5,7-dimeth0xy-3-ind0lyl acetic acid (A)5,7-dimeth0xygramine.A solution of 0.032 mole of 5,7-dirnethoxyindole in40 mls. of dioxane is added dropwise, over a period of 30 minutes, to anice-cooled, stirred mixture of 40 mls. of dioxane, 40 mls. of aceticacid, 3.2 mls. of 36% aqueous formaldehyde and 8.8 mls. of 25% aqueousdimethylamine. The clear solution is stirred and cooled for two hoursand then allowed to warm up to room temperature over night. To thissolution is added 500 mls. of water. The tunbid mixture is then treatedwith charcoal and filtered through a silicaceous filter aid. The clearfiltrate is made alkaline with 400 mls. of dilute sodium hydroxidesolution, and placed in a refrigerator, to cool. This mixture is thenfiltered and the solid gramine is washed with water and dried.

(B) 5,7-dimeth0xy-indolyl-3-acet0nitrile.-O.106 mole of the gramineobtained in A is added to 420 mls. of methyl iodide, with vigorousstirring, over a period of 20 minutes. The reaction mixture is thenallowed to remain at 5 for 15 hours. The solution is filtered and theiodine metholate cake is dried at 50. This solid is dissolved in asolution of gms. of sodium cyanide in 1 liter of water and warmed for 2hours at The desired product is extracted with chloroform which is thenevaporated to give a crude oily product. The oil is then dissolved in250 mls. of ether, filtered and the filtrate concentrated. Thisconcentrate is then diluted with petroleum ether, at which point the5,7-dimethoxy-indolyl-3-acetonitrile precipitates. The mixture is thenfiltered and the cake dried.

(C) 5,7-dimethoxy-ind0lyl 3 acetic acid.-0.08 mole of the nitrileobtained from B is added to a solution of 140 mls. of alcohol, mls. ofwater and 4.3 gms. of potassium hydroxide and refluxed for 15 hours. Themixture is brought to room temperature and 60 mls. of glacial aceticacid is added. The solution is then filtered through a talc filter andthe filtrate diluted with 500 mls. of water. The precipitated5,7-dimethoxy-indolyl-3-acetic acid is then filtered and dried.

(D) 1-nic0tinoyl-5,7-dimeth0xy-3-indol3 l acetic acid.- The procedure ofExample 46A, 46B, 46C and 46D are followed using the product of part Cof this example in place of the 6-methoxy-3-indolyl acetic acid, toproduce 1-nicotinoyl-5,7-dimethoxy-3-indolyl acetic acid. When5,6-dimethoxy-3-indolyl acetic acid is used in place of6-methoxy-3-indolyl acetic acid in the above procedure, there isobtained 1 nicotinoyl 5,6 dimethoxy-3-indolyl acetic acid.

When 5,6-methylenedioxyindole or 2-methy1-6-methoxyindole is used inplace of 5,7-dimethoxyindole in the procedure of parts A, B and C, thereis obtained Z-methyl- 6-methoxy-3-indolyl acetic acid or5,6-methylenedioxy-3- indolyl acetic acid, which, where used in theprocedure of part D give l-nicotinoyl 5,6 methylenedioxy 3-indolylacetic acid or 1-nicotinoyl-2methyl-6-methoxy-3-indolyl acetic acid.

EMMPLE 48 Methyl-4-benzyl0xy-3-ind0lyl acetate (A) 4-benzyl0xy-3-indolylacet0nitrile.The procedure of Example 47A and 47B is followed, using4-benzyloxyindole in place of the 5,7-dimethoxy-indole, to give4-benzyloxy-3-indolyl acetonitrile.

(B) Methyl 2(4-bertzyl0xy-ind0lyl-3)acetate.A mixture of 0.1 mole of(4-benzyloxy-indolyl-3)-acetonitrile in 150 ml. methanol, containing 30grams dry hydrogen chloride, is refluxed for 2 hours. The reactionmixture is taken to dryness and the residue distributed between 10%sodium bicarbonate solution and chloroform. The chloroform layer isdried with anhydrous sodium sulfate and taken to dryness in vacuo. Theresidue is reasonably pure ester.

Similarly, when 7-benzyloxy-3-indolyl acetonitrile is used instead ofthe 4-isorner, there is obtained methyl-7 benzyloxyl-S-indolyl acetate.When -benzyloxy indole and 6-benzyloxy indole are used in the procedureof parts A and B of this example, there are produced methyl 5-benzyloxy-3-indolyl acetate and methyl 6-benzyloxy-3- indolyl acetate.

EXAMPLE 49 1-nic0tinoyl-4-methoxy-3-indolyl acetic acid (A) Methyl4-hydr0xy-3-ind0lyl acetate.A solution of methyl 4-benzyloxy-3-indolylacetate (4.0 g.) in 150 ml. methanol is shaken with 3 g. palladium oncharcoal and hydrogen until the hydrogen uptake ceases. The catalyst isfiltered and the filtrate is taken to dryness in vacuo.

(B) Methyl 4-meth0xy-3-ind0lyl acetate.--A solution of methyl4hydroxy-3-indolyl acetate (10.5 gms., 0.065 m.) in 96 ml. sodiumhydroxide is stirred and treated with 7.5 ml. dimethyl sulfate. Afterstirring for several hours, the crude product is extracted with ether,washed with water and dried over sodium sulfate. The ether solution isevaporated in vacuo and the residue is chromatographed in 200 g. ofacid-washed alumina using a mixture of ether-petroleum ether (v./v.25-60%) as the eluent. r

(C) 4-methoxy-3-ind0lyl acetic acid.-A solution of methyl4-methoxy-3-indolyl acetate in excess 2 N absolute ethanolic potassiumhydroxide is allowed to stand overnight, diluted with water andextracted with ether. The aqueous layer is acidified. The precipitate iscollected and recrystallized from aqueous ethanol.

(D) 1-nicotinoyl-4-methoxy-3-ind0lyl acetic acid.--The procedure ofExamples 46A, 46B, 46C and 46D is followed using thep roduct of part Cin place of 6-methoxy-3- indolyl acetic acid, to produce1-nicrotinoyl-4-methoxy- 3-indolyl acetic acid.

EXAMPLE 50 1-nic0tin0yl-5-chl0r0-6-methoxy-d-indolyl acetic acid (A)5-chlor0-6-methoxy-S-indolyl acetic acid.-When5-chloro-6-methoxy-3-indolylacetonitrile is used in place of5,7-dimethoxy-indolyl-3-acetonitrile, in the procedure of Example 47C,there is obtained 5-chloro-6-methoxy-3- EXAMPLE 511-nic0tin0yl-2-methyl-4-meth0xy-3-ind0lyl acetic acid (A)2-methyl-4-methoxyindole- (1) 6-meth0xy-2-witr0benz0yl chloride-4.046mole of 6-methoxy-2-nitrobenzoic acid is added to 60 mls. of

'redistilled thionyl chloride and refluxed for 2 hours. The

excess reagent is removed under reduced pressure, maintaining thetemperature below 40. The residue is washed 25 with benzene and thenremoved under reduced pressure. This residue is placed over sodiumhydroxide, in vacuo overnight.

(2) Diazomethyl 6-meth0xy-2-nitr0phenylketone.A

solution of .044 mole of the 6-methoxy-2-nitrobenzoyl phenyl diazomethylketone is crystallized from this residue using dioxane.

(3) 6-methoxy-2-nitr0phenylacetic acid.A solution of .044 mole of thediazoketone obtained in (2) in 75 mls. of dioxane, is added over aperiod of 20 minutes to a freshly prepared solution of 4.0 gms. ofsilver oxide, 3.0 gms. of sodium thiosulfate and 5.0 grns. of sodiumcarbonate in 150 mls. distilled Water. The temperature of the reactionmixture is maintained at 5060 during the addition and for an additionalhour. At this point, the mixture is brought to a temperature of -95 for/2 hour. The mixture is then filtered and the filtrate is diluted with200. mls. of water, acidified with dilute nitric acid and extracted withchloroform (3x200 mls.). The combined chloroform extract is washed. with50 mls. of water and dried over sodium sulfate. The chloroform is thenremoved and the residue extracted with boiling water (2x100 mls.).Concentration of the water solution, followed by cooling, precipitatesthe 6-methoxy-2- nitrophenyl acetic acid.

(4) Ethyl-6-methoxy-2-nitr0phenylacetyl mal0natc. The product from A(3)is used in the procedure of part A(1) to give the corresponding acidchloride. A solution (0.02 mole) of this compound in 25 m1. of ether isgradually added to a refluxing ether solution of ethylethoxymagnesiomalonate. Heating is continued until stirring is difficultdue to formation of a viscous oil. The cooled mixture is then shakenwith dilute H 80 (2.5 g. in 20 ml. H O) until the oily magnesium complexhas dissolved. The ethereal phase is separated, washed with water, anddried over Na SO Evaporation yields the crudeethyl-6-methoxy-2-nitrophenylacetylmalonate.

(5) 6-meth0xy-2-nitrophertylacet0ne.--A solution of 5.7 gins. of theproduct from A(4), 12 mls. of acetic acid, 1.5 mls. of sulfuric acid and8 mls. of water is refluxed for 6 hours. The cooled solution is madealkaline with 5N sodium hydroxide and extracted with ether (3 X50 mls.).The combined ethereal extract is washed with water, dried over sodiumsulfate and evaporated to give an oil which rapidly solidifies.Crystallization of this solid from ethanol yields6-methoxy-2-nitrophenylacetone.

(6) 4-meth0xy-2-methy[indole-1.2 gms. of the product from A(5) is addedto a mixture of mls. of ethyl alcohol and 1.0 gm. of Raney nickel. Thissolution is shaken at room temperature and atmospheric pressure, inhydrogen for /2 hour. The solution is then filtered and the filtrateevaporated under reduced pressure. Crystallization from light petroleumether yields 4-methoxy2- methylindole.

r (B) Z-methyl-4-methoxy-3dnd0lyl acetic acid.When4-methoxy-2-methylindole is used in place of 5,7-dimethoxyindole asdescribed in Examples 47A, 47B and 47C, there is obtained2-methyl-4-methoxy-3-indolyl acetic acid.

(C) 1-nicotin0yl-2-methyl-4-meth0xy-3-ind0lyl acetic acid.-When theproduct from 51B is used in place of 6-methoXy-3-indolyl acetic acid asdescribed in Examples 46A, 46B, 46C and 46D, there is obtained1-nicotinoyl- 2-methyl-4-methoxy-3 -indolyl acetic acid.

EXAMPLE 52 1-Nic0tin0yl-7-mcth0xy-5-methyl-3-indolyl acetic acid (A) 7methaxy 5 methylindole.0.1, mole of 4,- methyl-o-anisidine is added to0.1 mole of monochloroacetaldehyde and the mixture refluxed for 2 hours.The water formed is distilled off and the residue is heated at 210220for an additional hour. This residue is then chromatographed onacid-washed alumina and eluted with ether:petroleum ether. The eluent isremoved under reduced pressure and 7-methoxy-5-methylindole is obtained.

(B) 1-nic0tin0yl-7-meth0xy-5-methyl-3-indolyl acetic acid.The productfrom part A is used in the procedures of Examples 46A, 46B, 46C and 46D.There is obtained 1-nicotinoyl-7-methoxy-5-methyl-3-indolyl acetic acid.

(C) 1 nictin0yl-5-flu0r0-7-methoxy-3-ind0lyl acetic acid.-The proceduresof parts A and B are followed, starting with 4-fiuoro-o-anisidine, togive 1-nicotinoyl-5- fiuoro-7-methoxy-3-indolyl acetic acid.

(D) 1 nicotirt'oly nitro 7 methoxy 3 indolyl acetic acid.The procedureof parts A and B are followed starting with 4-nitro-o-anisidine, to givel-nicotinoyl 5-nitro-7-methoxy-3-indolyl acetic acid. When this is usedin the procedure of Example 15, there is produced1-nicotinoyl-5-dimethylamino-7-rnethoxy-3-indolyl acetic acid.

EXAMPLE 53 1-nic0tin0yl-2-allyl-5-meth0vcy-3-ind0lyl acetic acid (A)S-methoxy-Z-indolyl acetaldehyde.--A solution of5-methoxy-2-indolylacetyl chloride (0.1 mole) in dry tetrahydrofuran istreated with 0.25 mole of lithium aluminium tri-t-butoxy hydride withice-cooling and stirring. After the initial reaction, the mixture isstirred at room temperature for 4 hours and poured into ice. Excess ofacetic acid is added and the product is extracted with ether. Theethereal solution is washed with sodium bicarbonate, dried over sodiumsulfate and evaporated to a syrup. Chromatography of the residue on acolumn of silica gel, using ether-petroleum ether (v./v.) -60% aseluent, gives 5-methoxy-2-indolyl acetaldehyde.

(B) 2-allyl-5-methoxy ind0le.A solution of 0.1 mole of the aldehyde and0.12 mole of methylene triphenylphosphine, prepared in situ from 0.12mole of methyl triphenylphosphonium iodide and 0.12 mole of n-butyllithium, in benzene is stirred at room temperature for 4 hours and thenat 80 for 1 hour. The solution is washed with 0.5 N hydrochloric acid,Water and dried over sodium sulfate. Evaporation of the solvent in vacuoand chromatography of the residue on a column of 300 g. acid-washedalumina, using ether-petroleum ether (v./"v.) 0-20% as eluent, gives2-allyl-5-methoxy indole.

(C) Z-allyl-5-meth0xygramvine.-A solution of 0.032 mole of2-.a1lyl-5-methoxy indole in 40 ml. of dioxane is added dropwise, overminutes, to an ice-cooled stirred mixture of ml. dioxane, 40 ml. aceticacid, 3.2 ml. 36% aqueous formaldehyde and 8.8 ml. 25% aqueousdimethylamine. The clear solution is stirred and cooled for two hoursand then allowed to warm to room temperature overnight. To this solutionis added 500 ml. of water. The turbid mixture is then treated withcharcoal and filtered through a silicaceous filter aid. The clearfiltrate is made alkaline with 400 ml. of dilute NaOH solution andcooled in a refrigerator. The mixture is filtered and the solid gramineis washed with water and dried.

(D) 2 allyl 5 methoxy 3'- indolyl acctonitrile.0.106 mole of the graminefrom part C is added to 420 ml. of methyl iodide, with vigorousstirring, over a period of 20 minutes. The reaction mixture is thenallowed to remain at 5 for 15 hours. The solution is filtered and theiodine metholate cake is dried at C. The solid is dissolved in asolution of g. NaCN in 1 liter and warmed for 2 hours at The desiredproduct is extracted with chloroform which is then evaporated to give acrude oily product. The oil is then dissolved in 250 ml. of ether,filtered and the filtrate is concentrated. The concentrate is dilutedwith petroleum ether, at which point the 2-allyl-5-methoxy-3-indolylacetonitrile precipitates. The mixture is filtered and the cake dried.

(E) Z-allyl 5 methoxy 3 indolyl acetic acid-0.08 mole of2-allyl-5-methoxy-3-indolyl acetonitrile is added to a mixture of 140ml. of alcohol, ml. of water and 4.3 g. of KOH. The mixture is refluxed15 hours and then brought to room temperature. Glacial acetic acid (60ml.) is added and the solution is filtered through a tale filter. Thefiltrate is diluted with 500 ml. of water and the precipitated24allyl-5-methoxy-3-indolyl acetic acid is separated by filtration anddried.

(F) 1 nicotinoyl 2 a llyl 5 methoxy 3 indolyl acetic acid.-T-heprocedure of Examples 47A, 47B, 47C and 47D is followed using theproduct of part E in place of the 6-methoxy-3-indolyl acetic acid, toproduce 1- nicotinoyl-2-allyl-5-methoxy-3-indolyl acetic acid.

EXAMPLE 54 1 (Z-aminonicotinoyl -2-methyl-5-meth0xy-3- indolyl aceticacid The procedure of Example 11 is followed, using 1-(2-nitronicotinoyl) 2 methyl 5 methoxy 3 indolyl acetic acid, (prepared inExample 8) in place of methyl(2-methyl-5-nitro-3-indolyl)acetate, toproduce 1-(2- aminonicotinoyl) 2 methyl 5 methoxy 3 indolyl acetic acid.

When the procedure of Example 15 (omitting the final bicarbonate wash)is followed using the 1-(2-nitronicotinoyl) compound from Example 8 inplace of the methyl (1 nicotinoyl 2 methyl 5 nitro 3 indolyl) acetateused therein, there is obtainedI-(Z-dimethylaminonicotinoyl)-2-methyl-5-methoxy-3-indolyl acetic acid.

When the procedure of Example 16 is followed, (omitting the finalbicarbonate wash) using the 1-(2-nitronicotinoyl) compound from Example8 in place of the S-nitro indolyl ester used therein, there is obtained1-(2- acetamino nicotinoyl) 2 methyl 5 methoxy 3- indolyl acetic acid.

What is claimed is:

1. A compound of the formula:

in which R is selected from the group consisting of pyridine, quinolineand substituted pyridine and quinoline radicals in which saidsubstituent is selected from the group consisting of halogen, loweralkyl, lower alkylthio, lower alkoxy, trifluoromethyl, phenoxy, loweralkyl phenoxy, lower alkanoyl, cyano, carb-lower alkoxy, carbamyl, loweralkylsulfonyl, benzylthio, phenylthio, lower alkylphenylthio, mercapto,nitro, amino, di- (lower alkyl)amino, lower alkanoylamino, hydroxy andbenzyloxy;

R is selected from the group consisting of hydrogen,

lower alkenyl and lower alkyl;

R is selected from the group consisting of hydrogen and lower alkyl;

R; is selected from the group consisting of hydrogen, lower alkyl, loweralkoxy, fluorine and trifluoromethyl;

R is selected from the group consisting of hydrogen, hydroxy, loweralkyl, lower alkoxy, nitro, amino, lower alkylamino, di(loweralkyl)amino, lower alkanoylamino, lower alkanoyl, lower alkylamino,bis(hydroxy lower alkyl)amino, l-pyrrolidino, 4-methyl-1-piperizinyl,4-morpholinyl, cyano, amino lower alkyl, dilower alkyl amino, loweralkyl, trifluoromethyl, halogen di(lower alkyl)sulfamyl, benzylthio,lower alkylbenzylthio, lower alkoxybenzylthio, halogenobenzylthio,benzyloxy, lower alkylbenzyloxy, lower alkoxybenzyloxy,

holagenobenzyloxy, lower alkenyl, lower alkenyloxy, l-azacyclopropyl,cyclopropyl(lower alkxy)methyloxy, and cyclobutyl(lowera-lkoxy)methyloxy; and

M is selected from the group consisting of OH, NH benzyloxy, loweralkoxy, OZ where Z is a cation and CY where Y represents the structure:

2. A compound of the formula:

R 0 H-C 0 0 H in which R and R are each lower alkyl and R is loweralkoxy.

3. A compound of the formula:

S CH3 in which R and R are each lower alkyl and R is lower alkoxy.

4. A compound of the formula:

in which R R and R are each lower alkyl.

5. A compound of the formula:

00H. in which R R and R are each lower alkyl.

6. A compound of the formula:

R5 CHa-GOOH I in which R is a lower alkyl and R is lower alkoxy.

7. A compound of the formula:

in which R is lower alkyl and R is di(lower al kyl) amino.

8. A compound of the formula:

TOTE-C0011 N R:

in which R is lower alkyl and R is lower alkoxy.

9. A compound of the formula:

R CHz-C 0 OH I (lb-Q01 References Cited by the Examiner UNITED STATESPATENTS 2,850,501 9/ 1958 Voegtli 2-60-294.9 3,161,654 12/1964 Shen260--31 9 WALTER A. MODANCE, Primary Examiner. ALAN L. ROTMAN, AssistantExaminer".

1. A COMPOUND OF THE FORMULA: